Treatment Of Cardiac Conditions

Abstract

The invention relates to the treatment of cardiac dysfunction. In particular, certain compounds, believed to be glucagon-GLP-1 dual agonist compounds, exert a positive inotropic effect while preserving the energy balance of the heart, and so may be superior to known inotropic agents such as dobutamine, norepinephrine and glucagon.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is the U.S. National Stage of PCT/DK2011/050018, filed Jan. 20, 2011, which, in turn, claims benefit of U.S. Patent Application No. 61/296,657, filed Jan. 20, 2010.

FIELD OF THE INVENTION

[0002] The invention relates to the use of compounds, typically glucagon-GLP-1 dual agonist compounds, as inotropic agents for the treatment of cardiac dysfunction.

BACKGROUND OF THE INVENTION

[0003] Positive inotropic agents are used to improve hemodynamic parameters and thereby relieve symptoms and protect end-organs in patients with myocardial infarction, heart failure or cardiogenic shock. The heart requires large amounts of chemical energy to support systolic and diastolic work. Therefore, by increasing cardiac work, inotropic agents also increase cardiac energy demand. However, the failing or diseased heart is usually energy starved (Ingwall, J S and Weiss, R G. Circ Res. 2004; 95: 135-145), and the use of inotropic agents may therefore result in energy depletion and ultimately increased mortality (Hamad, E et al. American Journal of Cardiovascular Drugs. 2007; 7: 235-248; White, C M. J Clin Pharmacol. 1999; 39: 442-447).

[0004] Preproglucagon is a 158 amino acid precursor polypeptide that is differentially processed in the tissues to form a number of structurally related proglucagon-derived peptides, including glucagon (Glu), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and oxyntomodulin (OXM). These molecules are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying and intestinal growth, as well as regulation of food intake.

[0005] A major biologically active fragment of GLP-1 is produced as a 30-amino acid, C-terminally amidated peptide that corresponds to amino acids 98 to 127 of preproglucagon. GLP-1 is produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, a hormone normally secreted by neuroendocrine cells of the gut in response to food. It increases insulin release by the beta cells even in subjects with long-standing type 2 diabetes. GLP-1 treatment has an advantage over insulin therapy because GLP-1 stimulates endogenous insulin secretion, which turns off when blood glucose levels drop. GLP-1 promotes euglycemia by increasing insulin release and synthesis, inhibiting glucagon release, and decreasing gastric emptying). GLP-1 (Hoist, J J. Physiol Rev. 2007; 87: 1409-1439), has been found to increase myocardial glucose uptake in an insulin-independent manner in normal and post-ischemic rat hearts (Zhao, T et al. J Pharmacol Exp Ther. 2006; 317: 1106-1113), isolated mouse hearts (Ban, K et al. Circulation. 2008; 117: 2340-2350), as well as in conscious dogs with dilated cardiomyopathy (Nikolaidis, L A et al. Am J Physiol Heart Circ Physiol. 2005; 289: H2401-H2408; Nikolaidis, L A et al. Circulation. 2004; 110: 955-961).

[0006] Glucagon is a 29-amino acid peptide that corresponds to amino acids 53 to 81 of pre-proglucagon and has the sequence His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-A- la-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr (Compound 1) (SEQ ID NO: 1). Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose--stored in the form of glycogen--through glycogenolysis. As these stores become depleted, glucagon stimulates the liver to synthesize additional glucose by gluconeogenesis. This glucose is released into the bloodstream, preventing the development of hypoglycemia.

[0007] Glucagon has a well documented inotropic effect on the heart (Buse, M G et al. J Biol Chem. 1973; 248: 697-706; Farah, A and Tuttle, R. J Pharmacol Exp Ther. 1960; 129: 49-55; Levey, G S and Epstein, S E. Circ Res. 1969; 24: 151-156; Mayer, S E et al. Circ Res. 1970; 26: 225-233).

[0008] Oxyntomodulin (OXM) is a 37 amino acid peptide which includes the complete 29 amino acid sequence of glucagon with an octapeptide carboxyterminal extension (amino acids 82 to 89 of pre-proglucagon, having the sequence Lys-Arg-Asn-Arg-Asn-Asn-He-Ala (Compound 2) (SEQ ID NO: 2) and termed "intervening peptide 1" or IP-1; the full sequence of human oxyntomodulin is thus His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-A- la-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala- ) (Compound 3) (SEQ ID NO: 3). OXM is released into the blood in response to food ingestion and in proportion to meal calorie content. OXM has been shown to suppress appetite and inhibit food intake in humans (Cohen et al, Journal of Endocrinology and Metabolism, 88, 4696-4701, 2003; WO 2003/022304). In addition to these anorectic effects, which are similar to those of GLP-1, OXM must also affect body weight by another mechanism, since rats treated with oxyntomodulin show less body weight gain than pair-fed rats (Bloom, Endocrinology 2004, 145, 2687).

[0009] OXM activates both the glucagon receptor and the GLP-1 receptor with a two-fold higher potency for the glucagon receptor over the GLP-1 receptor, but is less potent than native glucagon and GLP-1 on their respective receptors. Glucagon is also capable of activating both receptors, though with a strong preference for the glucagon receptor over the GLP-1 receptor. GLP-1 on the other hand is not capable of activating the glucagon receptor. The mechanism of action of oxyntomodulin is not well understood. In particular, it is not known whether the effects of the hormone are mediated exclusively through the glucagon receptor and the GLP-1 receptor, or through one or more as-yet unidentified receptors.

[0010] An eel analogue of oxyntomodulin appears to have an inotropic effect on eel heart (Uesaka et al, J Experimental Biol. 2001; 204, 3019-3026) and inotropic effects have also been documented for oxyntomodulin in mouse (Sowden et al. Am J Phys Regul Integr Comp Physiol. 2007; 292: R962-R970).

SUMMARY OF THE INVENTION

[0011] The present inventors have found that certain compounds can act as inotropic agents, more particularly positive inotropic agents, while having considerably less effect on the heart's energy status than known inotropic agents such as dobutamine, norepinephrine and glucagon. Consequently these compounds are more suitable for use as therapeutic agents than known inotropic agents.

[0012] Without wishing to be bound by any particular theory, the useful properties of these compounds may be due to their ability to activate both the glucagon receptor and the GLP-1 receptor. Thus, the compounds which can be used in the methods of the invention will be referred to as glucagon-GLP-1 dual agonists, or simply as "dual agonists".

[0013] Thus, the invention provides the use of a glucagon-GLP-1 dual agonist as a positive inotropic agent, in the treatment of heart disease or heart dysfunction.

[0014] The invention further provides a glucagon-GLP-1 dual agonist for use as a positive inotropic agent in the treatment of heart disease or heart dysfunction.

[0015] The invention further provides a glucagon-GLP-1 dual agonist for use in the preparation of a medicament for the treatment of heart disease or heart dysfunction, wherein the glucagon-GLP-1 dual agonist is to be administered for use as a positive inotropic agent.

[0016] The invention further provides the use of a glucagon-GLP-1 dual agonist in the preparation of a medicament for the treatment of heart disease or heart dysfunction, wherein the glucagon-GLP-1 dual agonist is to be administered for use as a positive inotropic agent.

[0017] The invention still further provides the use of a glucagon-GLP-1 agonists in the preparation of a medicament cabable of improving cardiac contractility without causing concomitant increase in heart rate.

[0018] The invention further provides a method of treatment of heart disease or heart dysfunction in a subject, comprising administering a glucagon-GLP-1 dual agonist to the subject as a positive inotropic agent.

[0019] Glucagon-GLP-1 dual agonists are well known in the art.

[0020] Oxyntomodulin is one example of a naturally-occurring dual agonist. Analogues of oxyntomodulin are described in WO2008/071972 and WO2007/100535.

[0021] Other dual agonists are described in WO2008/101017. The majority of those compounds are more similar in length to glucagon than OXM, being around 29 amino acids long, and so can be regarded as analogues of glucagon. However others are longer. Any of the dual agonists described in that document may be suitable for use as described herein. Further dual agonists are described in WO2009/155257 and WO2009/155258 and may also be suitable for use in the methods of the invention.

[0022] Still further dual agonists are described in WO2008/152403, PCT/GB2008/004132, PCT/GB2008/004121, PCT/GB2008/004157, PCT/GB2008/004130 and European patent application no. 09251780.4, and may also be suitable for use in the methods of the invention.

[0023] The dual agonist may be a compound having the formula:

R.sup.1--X--Z.sup.1--Z.sup.2--R.sup.2

wherein: R.sup.1 is hydrogen, C.sub.1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl;

X has the Formula I (SEQ ID NO: 105):

TABLE-US-00001 [0024] (SEQ ID NO: 105) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-Tyr-Leu-X15-X16-X17-X18-Ala-X- 20-X21-Phe- X23-X24-Trp-Leu-X27-X28-X29

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, acetyl-His, homo-His, alpha,alpha-dimethyl imidiazole acetic acid (DMIA), N-methyl His, alpha-methyl His or imidazole acetic acid;

X2 is Ser, Aib or D-Ser;

X3 is Gln, Glu, Orn or Nle;

X10 is Tyr or Trp;

X12 is Lys, Arg, His, Ala, Leu, Dpu, Dpr, Orn, Citrulline or Ornithine;

[0025] X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid; X16 is Ser, Thr, Lys, Arg, His, Glu, Asp, Ala, Gly, Gln, homoglutamic acid or homocysteic acid; X17 is Arg, Lys, His, Glu, Gln, Ala, Leu, Dpu, Dpr, Orn, Cys, homocysteine or acetyl phenylalanine; X18 is Arg, Lys, His, Tyr, Ala, Ser, Leu, Cys, Orn, homocysteine or acetyl phenylalanine;

X20 is Gln, Lys, Arg, His, Glu, Asp, Ala, Cys, Orn or Citrulline;

[0026] X21 is Asp, Glu, Gln, Lys, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val, Ile or Leu;

[0027] X24 is Gln, Lys, Arg, Glu, Asp, Ser, Ala, Leu, Cys, Orn, homocysteine or acetyl phenyalanine; X27 is Met, Lys, Arg, Glu, Leu, Nle, Cys or absent; X28 is Asn, Lys, Arg, Glu, Asp, Ser, Ala, Leu, Cys, Citrulline, Orn, or absent; X29 is Thr, Lys, Arg, Glu, Ser, Ala, Gly, Cys, Orn, homocysteine, acetyl phenyalanine or absent;

R.sup.2 is NH.sub.2 or OH;

[0028] Z.sup.1 is absent or has the sequence:

TABLE-US-00002 (SEQ ID NO: 339) GlyProSerSerGlyAlaProProProSer; (SEQ ID NO: 340) GlyProSerSerGlyAlaProProProSerCys; (SEQ ID NO: 341) LysArgAsnArgAsnAsnIleAla; or (SEQ ID NO: 342) LysArgAsnArg;

Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; wherein, if Z.sup.1 is present, X27, X28 and X29 are also present; and if Z.sup.1 is absent, the compound has a substitution or deletion relative to human glucagon at one or more of positions X1, X2, X3, X10, X12, X15, X16, X17, X18, X20, X21, X23, X24, X27, X28 and X29; or a pharmaceutically acceptable salt or derivative thereof; wherein said compound has higher GLP-1 receptor selectivity than human glucagon.

[0029] Independently, where present, Z.sup.2 may be or comprise one or more amino acid residues. For example, Z.sup.2 may be a .gamma.-Glu (also denoted isoGlu), Glu, .beta.-Ala or .epsilon.-Lys residue, or a 4-aminobutanoyl, 8-aminooctanoyl or 8-amino-3,6-dioxaoctanoyl moiety.

[0030] The compound may have the formula R.sup.1--X--Z.sup.2--R.sup.2

wherein R.sup.1 is hydrogen, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R.sup.2 is OH or NH.sub.2;

[0031] X is a peptide which has the Formula II

TABLE-US-00003 (SEQ ID NO: 4) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-Arg-Ala-Arg-Ala-Asp-Asp-Phe-Val-Ala- Trp-Leu-Lys-Glu-Ala (Compound 4)

or differs from Formula II at up to 4 of the following positions whereby, if different from Formula I: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is: Lys, Asp, Glu; the residue at position 18 is selected from: Lys, His, Ala, Ser, Tyr; the residue at position 20 is selected from: Gln, His, Lys, Arg, Glu; the residue at position 21 is: Glu; the residue at position 24 is selected from: Gln, Leu, Glu, Lys, Arg, Asp; the residue at position 27 is selected from: Met, Cys, Arg, Glu, Leu or is absent; the residue at position 28 is selected from: Asn, Ser, Arg, Lys, Ala, Leu, Glu, Asp or is absent; and the residue at position 29 is selected from: Thr, Glu, Lys or is absent; and Z.sup.2 is absent or is a sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof,

[0032] In some embodiments, X may differ from Formula II at up to 4 of the following positions whereby, if different from Formula II:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 18 is selected from: Lys, His, Ala, Ser, Tyr; the residue at position 20 is selected from: Gln, His, Lys, Arg, Glu; the residue at position 24 is selected from: Gln, Leu, Glu, Lys, Arg; the residue at position 27 is selected from: Met, Cys, Arg, Glu, Leu; the residue at position 28 is selected from: Asn, Ser, Arg, Lys, Ala, Leu; and the residue at position 29 is selected from: Thr, Glu, Lys.

[0033] In other embodiments, X comprises the residues 27-Lys and 28-Ser. In such cases, X may additionally differ from Formula II at one or two of the following positions whereby, if different from Formula II:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 18 is selected from: Lys, His, Ala, Ser, Tyr; the residue at position 20 is selected from: Gln, His, Lys, Arg, Glu; the residue at position 24 is selected from: Gln, Leu, Glu, Lys, Arg; and the residue at position 29 is selected from: Thr, Glu, Lys.

[0034] In any of the embodiments described above, the residues at positions 16 and 20 may be capable of forming a salt bridge. Examples of suitable pairs of residues include:

16-Asp, 20-Lys;

16-Glu, 20-Lys;

16-Asp, 20-Arg;

16-Glu, 20-Arg;

16-Lys, 20-Asp;

16-Arg, 20-Asp;

16-Lys, 20-Glu; and

16-Arg, 20-Glu.

[0035] While maintaining consistency with the definitions above, it may be desirable that X comprises one or more of the following sets of residues:

16-Arg;

16-Arg, 20-Asp;

16-Arg, 20-Asp, 24-Ala;

16-Arg, 20-Asp, 27-Lys, 28-Ser;

16-Arg, 20-Asp, 29-Ala;

16-Arg, 27-Lys, 28-Ser;

16-Arg, 27-Lys, 28-Ser, 29-Ala;

24-Ala, 27-Lys, 28-Ser;

24-Ala, 27-Lys, 28-Ser, 29-Ala;

24-Ala;

27-Lys;

28-Ser;

20-Glu, 28-Ser, 29-Thr;

24-Glu, 28-Ser, 29-Thr;

27-Glu, 28-Arg;

2-D-Ser, 28-Ser, 29-Thr; or

20-His, 28-Ser, 29-Thr.

[0036] For example, X may have the sequence:

TABLE-US-00004 (SEQ ID NO: 5) HSQGTFTSDYSKYLDRARADDFVAWLKSA; (Compound 5) (SEQ ID NO: 6) HSQGTFTSDYSKYLDRARADDFVAWLKEA; (Compound 6) (SEQ ID NO: 7) HSQGTFTSDYSKYLDRARAEDFVAWLKST; (Compound 7) (SEQ ID NO: 8) HSQGTFTSDYSKYLDRARADDFVEWLKST; (Compound 8) (SEQ ID NO: 9) HSQGTFTSDYSKYLDRARADDFVAWLERA; (Compound 9) (SEQ ID NO: 10) H-DSer-QGTFTSDYSKYLDRARADDFVAWLKST; (Compound 10) (SEQ ID NO: 11) HSQGTFTSDYSKYLDRARAHDFVAWLKST; (Compound 11) or (SEQ ID NO: 12) HSQGTFTSDYSKYLDRARADDFVAWLKST. (Compound 12)

[0037] The peptides defined by Formula II may carry one or more intramolecular bridge within the peptide sequence X. Each such bridge may suitably be formed between the side chains of two amino acid residues of X which are typically separated by three amino acids in the linear sequence of X (i.e. between amino acid A and amino acid A+4).

[0038] More particularly, the bridges may be formed between the side chains of residue pairs 12 and 16, 16 and 20, 17 and 21, 20 and 24, or 24 and 28. The two side chains can be linked to one another through ionic interactions or by covalent bonds. Thus these pairs of residues may comprise oppositely charged side chains in order to form a salt bridge by ionic interactions. For example, one of the residues may be Glu or Asp, while the other may be Lys or Arg. The pairings of Lys and Glu and Lys and Asp, may also be capable of reacting to form a lactam ring. Likewise, a Tyr and a Glu or a Tyr and an Asp are capable of forming a lactone ring.

[0039] In particular, residues at positions 16 and 20 may be capable of forming an intramolecular bridge. Examples of suitable pairs of residues at these positions include:

16-Asp, 20-Lys;

16-Glu, 20-Lys;

16-Asp, 20-Arg;

16-Glu, 20-Arg;

16-Lys, 20-Asp;

16-Arg, 20-Asp;

16-Lys, 20-Glu; and

16-Arg, 20-Glu.

[0040] The compound may have the formula R.sup.1--X--Z.sup.2--R.sup.2

wherein R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R.sup.2 is OH or NH.sub.2;

[0041] X is a peptide which has the Formula III:

TABLE-US-00005 (SEQ ID NO: 13) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Leu- Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Lys-Asp-Phe-Ile-Glu- Trp-Leu-Glu-Ser-Ala (Compound 13)

or differs from Formula III at up to 4 of the following positions whereby, if different from Formula III: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly, Asp; the residue at position 17 is selected from: Lys, Leu; the residue at position 18 is selected from: Lys, His, Ala, Ser, Tyr; the residue at position 20 is selected from: Gln, His, Arg, Glu, Asp; the residue at position 21 is: Glu; the residue at position 23 is selected from: Val, Leu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Leu or is absent; the residue at position 28 is selected from: Asn, Arg, Lys, Glu, Ala, Leu, Asp or is absent; and the residue at position 29 is selected from: Thr, Glu, Lys or is absent; and Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, X differs from Formula III at up to 4 of the following positions whereby, if different from Formula III:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly; the residue at position 17 is selected from: Lys, Leu; the residue at position 18 is selected from: Lys, His, Ala, Ser, Tyr; the residue at position 23 is selected from: Val, Leu; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Leu; the residue at position 28 is selected from: Asn, Arg, Lys, Glu, Ala, Leu; and the residue at position 29 is selected from: Thr, Glu, Lys;

[0043] In some embodiments, X differs from Formula III at up to 4 of the following positions whereby, if different from Formula III:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly; the residue at position 17 is selected from: Lys, Leu; the residue at position 18 is selected from: Lys, His, Ala, Ser, Tyr; and the residue at position 23 is selected from: Val, Leu.

[0044] In some embodiments, X differs from Formula III at up to 4 of the following positions whereby, if different from Formula III:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 23 is selected from: Val, Leu; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Leu; the residue at position 28 is selected from: Asn, Arg, Lys, Glu, Ala, Leu; and the residue at position 29 is selected from: Thr, Glu, Lys.

[0045] While maintaining consistency with the definitions above, it may be desirable that X comprises one or more of the following sets of residues:

20-Lys, 24-Glu;

20-Lys, 24-Glu, 29-Ala;

20-Lys, 23-Ile, 24-Glu;

27-Glu, 28-Ser, 29-Ala;

29-Ala;

20-Gln;

23-Val;

24-Gln;

29-Thr;

27-Met, 28-Asn, 29-Thr;

20-Gln, 23-Val, 24-Gln;

20-Glu, 24-Lys; or

28-Arg.

[0046] For example, X may have the sequence:

TABLE-US-00006 (SEQ ID NO: 14) HSQGTFTSDYSLYLDSRRAQDFIEWLESA; (Compound 14) (SEQ ID NO: 15) HSQGTFTSDYSLYLDSRRAKDFVEWLESA; (Compound 15) (SEQ ID NO: 16) HSQGTFTSDYSLYLDSRRAKDFIQWLESA; (Compound 16) (SEQ ID NO: 17) HSQGTFTSDYSLYLDSRRAKDFIEWLEST; (Compound 17) (SEQ ID NO: 18) HSQGTFTSDYSLYLDSRRAKDFIEWLMNT; (Compound 18) (SEQ ID NO: 19) HSQGTFTSDYSLYLDSRRAQDFVQWLESA; (Compound 19) (SEQ ID NO: 20) HSQGTFTSDYSLYLDSRRAEDFIKWLESA; (Compound 20) or (SEQ ID NO: 21) HSQGTFTSDYSLYLDSRRAKDFIEWLERA. (Compound 21)

[0047] The peptides defined by Formula III may carry one or more intramolecular bridges within the peptide sequence X. Each such bridge may suitably be formed between the side chains of two amino acid residues of X which are typically separated by three amino acids in the linear sequence of X (i.e. between amino acid A and amino acid A+4).

[0048] More particularly, the bridge may be formed between the side chains of residue pairs 16 and 20, 17 and 21, 20 and 24, or 24 and 28. The two side chains can be linked to one another through ionic interactions, or by covalent bonds. Thus these pairs of residues may comprise oppositely charged side chains in order to form a salt bridge by ionic interactions. For example, one of the residues may be Glu or Asp, while the other may be Lys or Arg. The pairings of Lys and Glu and Lys and Asp, may also be capable of reacting to form a lactam ring. Likewise, a Tyr and a Glu or a Tyr and a Asp are capable of forming a lactone ring.

[0049] In particular, the residues at positions 20 and 24 may be capable of forming an intramolecular bridge. Examples of suitable pairs of residues at these positions include:

20-Asp, 24-Lys;

20-Glu, 24-Lys;

20-Asp, 24-Arg;

20-Glu, 24-Arg;

20-Lys, 24-Asp;

20-Arg, 24-Asp;

20-Lys, 24-Glu; and

20-Arg, 24-Glu.

[0050] Without wishing to be bound by any particular theory, it is believed that such intramolecular bridges stabilise the alpha helical structure of the molecule and so increase potency and/or selectivity at the GLP-1 receptor and possibly also at the glucagon receptor.

[0051] The compound may have the formula R.sup.1--X--Z.sup.2--R.sup.2 wherein

R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R.sup.2 is OH or NH.sub.2;

[0052] X is a peptide which has the Formula IV:

TABLE-US-00007 (SEQ ID NO: 22) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Lys-Asp-Phe-Ile-Glu- Trp-Leu-Leu-Ser-Ala (Compound 22)

or differs from Formula IV at up to 4 of the following positions whereby, if different from Formula IV: the residue at position 2 is selected from: D-Ser, Aib; the residue at position 16 is selected from: Ser, Asp, Lys, Arg; the residue at position 18 is: Ala; the residue at position 20 is selected from: Gln, Arg, Glu, Asp; the residue at position 21 is: Glu; the residue at position 23 is: Val; the residue at position 24 is selected from: Gln, Asp, Lys, Arg, Ala; the residue at position 27 is selected from: Met, Cys, Lys or is absent; the residue at position 28 is selected from: Asn, Arg, Lys, Ala, Glu, Asp or is absent; and the residue at position 29 is selected from: Thr, Arg or is absent; and Z.sup.2 is absent or a sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, X differs from Formula IV at up to 4 of the following positions whereby, if different from Formula IV:

the residue at position 2 is selected from: D-Ser, Aib; the residue at position 16 is selected from: Ser, Asp, Lys; the residue at position 20 is selected from: Gln, Arg, Glu; the residue at position 27 is selected from: Met, Cys, Lys; and the residue at position 28 is selected from: Asn, Arg, Ala.

[0054] In some of those embodiments, X may differ from Formula IV at up to 3 of the following positions whereby, if different from Formula IV:

the residue at position 2 is selected from: D-Ser, Aib; the residue at position 16 is selected from: Ser, Asp, Lys; and the residue at position 20 is selected from: Gln, Arg, Glu.

[0055] In alternative embodiments, X may differ from Formula IV at up to 4 of the following positions whereby, if different from Formula IV:

the residue at position 2 is selected from: D-Ser, Aib; the residue at position 16 is selected from: Ser, Asp, Lys; the residue at position 18 is: Ala; and the residue at position 20 is selected from: Gln, Arg, Glu.

[0056] In still further alternative embodiments, X may differ from Formula IV at up to 4 of the following positions whereby, if different from Formula IV:

the residue at position 23 is: Val; the residue at position 24 is selected from: Gln, Asp, Lys, Arg, Ala; the residue at position 27 is selected from: Met, Cys, Lys; and the residue at position 28 is selected from: Asn, Arg, Ala.

[0057] In any of the embodiments described above, the residues at positions 16 and 20 may be capable of forming a salt bridge. Examples of suitable pairs of residues include:

16-Asp, 20-Lys;

16-Glu, 20-Lys;

16-Asp, 20-Arg;

16-Glu, 20-Arg;

16-Lys, 20-Asp;

16-Arg, 20-Asp;

16-Lys, 20-Glu;

16-Arg, 20-Glu.

[0058] Additionally or alternatively, the residues at positions 20 and 24 may be capable of forming a salt bridge. Examples of suitable pairs of residues include:

20-Asp, 24-Lys;

20-Glu, 24-Lys;

20-Asp, 24-Arg;

20-Glu, 24-Arg;

20-Lys, 24-Asp;

20-Arg, 24-Asp;

20-Lys, 24-Glu;

20-Arg, 24-Glu.

[0059] While maintaining consistency with the definitions above, it may be desirable that X comprises one or more of the following sets of residues:

20-Lys, 24-Glu;

20-Lys, 23-Ile, 24-Glu;

16-Glu, 20-Lys, 24-Glu;

16-Glu, 20-Lys;

16-Glu, 20-Lys, 29-Ala;

16-Glu, 20-Lys, 23-Ile, 24-Glu;

16-Glu, 20-Lys, 23-Ile, 24-Glu, 29-Ala;

16-Glu, 20-Lys, 24-Glu, 29-Ala;

20-Lys, 23-Ile, 24-Glu, 29-Ala;

27-Leu, 28-Ser, 29-Ala;

29-Ala;

16-Ser;

20-Gln;

23-Val;

24-Gln;

16-Ser, 20-Gln;

16-Asp, 20-Arg, 24-Asp;

16-Lys, 20-Glu;

24-Arg; or

28-Arg.

[0060] For example, X may have the sequence:

TABLE-US-00008 (SEQ ID NO: 23) HSQGTFTSDYSKYLDERRAQDFIEWLLSA; (Compound 23) (SEQ ID NO: 24) HSQGTFTSDYSKYLDERRAKDFVEWLLSA; (Compound 24) (SEQ ID NO: 25) HSQGTFTSDYSKYLDERRAKDFIQWLLSA; (Compound 25) (SEQ ID NO: 26) HSQGTFTSDYSKYLDSRRAQDFIEWLLSA; (Compound 26) (SEQ ID NO: 27) HSQGTFTSDYSKYLDDRRARDFIDWLLSA; (Compound 27) (SEQ ID NO: 28) HSQGTFTSDYSKYLDKRRAEDFIKWLLSA; (Compound 28) (SEQ ID NO: 29) HSQGTFTSDYSKYLDERRAKDFIRWLLSA; (Compound 29) (SEQ ID NO: 30) HSQGTFTSDYSKYLDERRAKDFIEWLLRA; (Compound 30) (SEQ ID NO: 31) HSQGTFTSDYSKYLDSRRAKDFIEWLLSA; (Compound 31) (SEQ ID NO: 32) HSQGTFTSDYSKYLDERAAKDFIEWLLSA; (Compound 32) (SEQ ID NO: 33) HSQGTFTSDYSKYLDERRAKDFIDWLLSA; (Compound 33) (SEQ ID NO: 34) HSQGTFTSDYSKYLDERRAKDFIEWLLAA; (Compound 34) or (SEQ ID NO: 35) HSQGTFTSDYSKYLDERRAKDFIEWLLSA. (Compound 35)

[0061] The peptides defined by Formula IV may carry one or more intramolecular bridge within the peptide sequence X. Each such bridge may suitably be formed between the side chains of two amino acid residues of X which are typically separated by three amino acids in the linear sequence of X (i.e. between amino acid A and amino acid A+4).

[0062] More particularly, the bridge may be formed between the side chains of residue pairs 12 and 16, 16 and 20, 17 and 21, 20 and 24, or 24 and 28. The two side chains can be linked to one another through ionic interactions, or by covalent bonds. Thus these pairs of residues may comprise oppositely charged side chains in order to form a salt bridge by ionic interactions. For example, one of the residues may be Glu or Asp, while the other may be Lys or Arg. The pairings of Lys and Glu and Lys and Asp, may also be capable of reacting to form a lactam ring. Likewise, a Tyr and a Glu or a Tyr and a Asp are capable of forming a lactone ring.

[0063] In particular, the residues at positions 16 and 20, and/or 20 and 24 may be capable of forming an intramolecular bridge. Examples of suitable pairs of residues at these positions include:

16-Asp, 20-Lys;

16-Glu, 20-Lys;

16-Asp, 20-Arg;

16-Glu, 20-Arg;

16-Lys, 20-Asp;

16-Arg, 20-Asp;

16-Lys, 20-Glu;

[0064] 16-Arg, 20-Glu; and/or

20-Asp, 24-Lys;

20-Glu, 24-Lys;

20-Asp, 24-Arg;

20-Glu, 24-Arg;

20-Lys, 24-Asp;

20-Arg, 24-Asp;

20-Lys, 24-Glu;

20-Arg, 24-Glu.

[0065] Without wishing to be bound by any particular theory, it is believed that such intramolecular bridges stabilise the alpha helical structure of the molecule and so increase potency and/or selectivity at the GLP-1 receptor and possibly also the glucagon receptor.

[0066] The compound may have the formula R.sup.1--X--Z.sup.2--R.sup.2

wherein R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R.sup.2 is OH or NH.sub.2;

[0067] X is a peptide which has the Formula V:

TABLE-US-00009 (SEQ ID NO: 36) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-Ser-Lys-Ala-Ala-His-Asp-Phe-Val-Glu- Trp-Leu-Leu-Arg-Ala (Compound 36)

or differs from Formula V at up to 4 of the following positions whereby, if different from Formula V: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 12 is selected from: Leu, Arg, Dpu, Dpr, Orn; the residue at position 16 is selected from: Arg, His, Lys, Glu, Asp; the residue at position 17 is selected from: Arg, Leu, Dpu, Dpr, Orn; the residue at position 18 is selected from: Arg, Lys, His, Ser, Tyr; the residue at position 20 is selected from: Gln, Lys, Arg, Glu, Asp; the residue at position 21 is Glu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu or is absent; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu, Asp or is absent; and the residue at position 29 is selected from: Thr, Glu, Lys or is absent; and Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

[0068] In certain embodiments of this aspect, X may differ from Formula V at up to 4 of the following positions whereby, if different from Formula V:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu; the residue at position 17 is selected from: Arg, Leu; the residue at position 18 is selected from: Arg, Lys, His, Ser, Tyr; the residue at position 20 is selected from: Gln, Lys, Arg, Glu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu; and the residue at position 29 is selected from: Thr, Glu, Lys.

[0069] In certain embodiments of this aspect, X may differ from Formula V at up to 4 of the following positions whereby, if different from Formula V:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu; and the residue at position 29 is selected from: Thr, Glu, Lys.

[0070] While maintaining consistency with the definitions relating to Formula V above, it may be desirable that X comprises one or more of the following sets of residues:

17-Lys, 18-Ala;

17-Leu, 18-Ala;

17-Lys, 18-Ala, 20-His;

17-Leu, 18-Ala, 20-His;

17-Lys, 18-Ala, 24-Glu;

17-Leu, 18-Ala, 24-Glu;

17-Lys, 18-Ala, 27-Leu;

17-Leu, 18-Ala, 27-Leu;

17-Lys, 18-Ala, 29-Ala;

17-Leu, 18-Ala, 29-Ala;

17-Lys, 18-Ala, 27-Leu, 29-Ala;

17-Leu, 18-Ala, 27-Leu, 29-Ala;

17-Lys, 18-Ala, 27-Leu, 28-Arg, 29-Ala;

17-Leu, 18-Ala, 27-Leu, 28-Arg, 29-Ala;

24-Glu, 28-Arg;

24-Glu, 28-Arg, 27-Leu;

24-Glu, 28-Arg, 27-Leu, 29-Ala;

27-Leu, 28-Arg, 29-Ala;

29-Ala;

20-Arg, 24-Arg, 27-Lys, 28-Leu;

17-Arg;

18-Arg;

20-Gln;

24-Gln;

27-Met, 28-Asn, 29-Thr; or

24-Lys

[0071] and combinations thereof.

[0072] For example, X may have the sequence:

TABLE-US-00010 (SEQ ID NO: 37) HSQGTFTSDYSKYLDSKAARDFVRWLKLA; (Compound 37) (SEQ ID NO: 38) HSQGTFTSDYSKYLDSRAAHDFVEWLLRA; (Compound 38) (SEQ ID NO: 39) HSQGTFTSDYSKYLDSKRAHDFVEWLLRA; (Compound 39) (SEQ ID NO: 40) HSQGTFTSDYSKYLDSKAAQDFVEWLLRA; (Compound 40) (SEQ ID NO: 41) HSQGTFTSDYSKYLDSKAAHDFVQWLLRA; (Compound 41) (SEQ ID NO: 42) HSQGTFTSDYSKYLDSKAAHDFVEWLMNT; (Compound 42) (SEQ ID NO: 43) HSQGTFTSDYSKYLDSKAAHDFVKWLLRA; (Compound 43) (SEQ ID NO: 44) H-DSer-QGTFTSDYSKYLDSKAAHDFVEWLLRA; (Compound 44) (SEQ ID NO: 45) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA; (Compound 45) (SEQ ID NO: 46) HSQGTFTSDYSKYLDSKAAKDFVEWLLRA; (Compound 46) (SEQ ID NO: 47) HSQGTFTSDYSKYLDKKAAHDFVEWLLRA (Compound 47) or (SEQ ID NO: 48) HSQGTFTSDYSKYLDSKAAHDFVEWLLRA. (Compound 48)

[0073] In an alternative aspect, the compound may have the formula R.sup.1--X--Z.sup.2--R.sup.2

wherein R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R.sup.2 is OH or NH.sub.2;

[0074] X is a peptide which has the Formula VI:

TABLE-US-00011 (SEQ ID NO: 49) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-Ser-Lys-Ala-Ala-His-Asp-Phe-Val-Glu- Trp-Leu-Leu-Arg-Ala (Compound 49)

or differs from Formula VI at up to 5 of the following positions whereby, if different from Formula VI: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu; the residue at position 17 is: Arg, Leu, Dpu, Dpr, Orn; the residue at position 20 is selected from: Gln, Lys, Arg, Glu, Asp; the residue at position 21 is Glu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu or is absent; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu, Asp or is absent; and the residue at position 29 is selected from: Thr, Glu, Lys or is absent; and Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

[0075] In certain embodiments of this aspect, X may differ from Formula VI at up to 4 of the following positions whereby, if different from Formula VI:

the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly; the residue at position 17 is selected from: Arg, Leu; the residue at position 18 is selected from: Arg, Lys, His, Ser, Tyr; the residue at position 20 is selected from: Gln, Lys, Arg, Glu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu; and the residue at position 29 is selected from: Thr, Glu, Lys.

[0076] While maintaining consistency with the definitions in relation to Formula VI above, it may be desirable that X comprises any of the sets of residues described above in relation to the first aspect, or one or more of the following sets of residues:

20-Gln, 24-Gln, 27-Met, 28-Asn, 29-Thr; or

17-Leu, 20-Gln, 24-Gln, 28-Asn, 29-Thr.

[0077] X may have the sequence:

TABLE-US-00012 (SEQ ID NO: 50) HSQGTFTSDYSKYLDSKAAQDFVQWLMNT (Compound 50) or (SEQ ID NO: 51) HSQGTFTSDYSKYLDSLAAQDFVQWLLNT. (Compound 51)

[0078] The peptides defined by Formulae V and VI may carry one or more intramolecular bridge within the peptide sequence X. Each such bridge may suitably be formed between the side chains of two amino acid residues of X which are typically separated by three amino acids in the linear sequence of X (i.e. between amino acid A and amino acid A+4).

[0079] More particularly, the bridge may be formed between the side chains of residue pairs 12 and 16, 16 and 20, 17 and 21, 20 and 24, or 24 and 28. The two side chains can be linked to one another through ionic interactions or by covalent bonds. Thus these pairs of residues may comprise oppositely charged side chains in order to form a salt bridge by ionic interactions. For example, one of the residues may be Glu or Asp, while the other may be Lys or Arg. The pairings of Lys and Glu and Lys and Asp, may also be capable of reacting to form a lactam ring. Likewise, a Tyr and a Glu or a Tyr and a Asp are capable of forming a lactone ring.

[0080] In particular, residues at positions 16 and 20 may be capable of forming an intramolecular bridge. Examples of suitable pairs of residues at these positions include:

16-Asp, 20-Lys;

16-Glu, 20-Lys;

16-Asp, 20-Arg;

16-Glu, 20-Arg;

16-Lys, 20-Asp;

16-Arg, 20-Asp;

16-Lys, 20-Glu; and

16-Arg, 20-Glu.

[0081] Without wishing to be bound by any particular theory, it is believed that such intramolecular bridges stabilise the alpha helical structure of the molecule and so increase potency and/or selectivity at the GLP-1 receptor and possibly also the glucagon receptor.

[0082] Without wishing to be bound by any particular theory, the arginine residues at positions 17 and 18 of native glucagon appear to provide significant selectivity for the glucagon receptor. A hydrophobic residue (e.g. Ala) at position 18 may also increase potency at both GLP-1 and glucagon receptors. It may also increase enzymatic stability compared to native glucagon.

[0083] Without wishing to be bound by any particular theory, the residues at positions 27, 28 and 29 of native glucagon appear to provide significant selectivity for the glucagon receptor. Substitutions at one, two, or all three of these positions with respect to the native glucagon sequence may increase potency at and/or selectivity for the GLP-1 receptor, potentially without significant reduction of potency at the glucagon receptor. Particular examples include Leu or Lys at position 27, Arg or Ser at position 28 and Ala at position 29.

[0084] Substitution of the naturally-occurring Met residue at position 27 (e.g. with Leu, Lys, Arg or Glu) also reduces the potential for oxidation, so increasing the chemical stability of the compounds.

[0085] Substitution of the naturally-occurring Asn residue at position 28 (e.g. by Glu, Ser, Arg, Lys, Ala or Leu) also reduces the potential for deamidation in acidic solution, so increasing the chemical stability of the compounds.

[0086] Potency and/or selectivity at the GLP-1 receptor may also be increased by introducing residues that are likely to form an amphipathic helical structure, potentially without significant loss of potency at the glucagon receptor. This may be achieved by introduction of charged residues at one or more of positions 16, 20, 24, and 28. Thus the residues of positions 16 and 20 may all be charged, the residues at positions 16, 20, and 28 may all be charged, or the residues at positions 16, 20, 24, and 28 may all be charged. The presence of charged residues at position 16 and 20 may be particularly desirable when they are capable of forming an intramolecular bridge, e.g. when they are oppositely charged amino acids, such as Arg at position 16 and Asp or Glu at position 20 or Glu at position 16 and His or Lys at position 20.

[0087] Substitution of one or both of the naturally-occurring Gln residues at positions 20 and 24 also reduces the potential for deamidation in acidic solution, so increasing the chemical stability of the compounds. For example, the compounds may have Asp or His at position 20 and Ala in position 24, optionally also with Ser, Glu or Arg at position 28.

The compound may have the formula R.sup.1--X--Z.sup.1--Z.sup.2--R.sup.2 wherein: R.sup.1 is hydrogen, C.sub.1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl; wherein X has the Formula VII:

TABLE-US-00013 (SEQ ID NO: 343) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-Tyr- Leu-X15-X16-X17-X18-Ala-X20-X21-Phe-X23-X24-Trp- Leu-X27-X28-X29

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, acetyl-His, homo-His, alpha,alpha-dimethyl imidiazole acetic acid (DMIA), N-methyl His, alpha-methyl His, or imidazole acetic acid; X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, aminoisobutyric acid (Aib) or N-methyl Ala;

X3 is Gln, Glu, Orn or Nle;

X10 is Tyr or Trp;

X12 is Lys, Citrulline, Orn or Arg;

[0088] X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid; X17 is Arg, Gln, Lys, Cys, Orn, homocysteine or acetyl phenylalanine; X18 is Arg, Ala, Lys, Cys, Orn, homocysteine or acetyl phenylalanine;

X20 is Gln, Lys, Arg, Orn or Citrulline;

[0089] X21 is Gln, Glu, Asp, Lys, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val or Ile;

[0090] X24 is Ala, Gln, Glu, Lys, Cys, Orn, homocysteine or acetyl phenyalanine;

X27 is Met, Leu or Nle;

X28 is Asn, Arg, Citrulline, Orn, Lys or Asp;

[0091] X29 is Thr, Gly, Lys, Cys, Orn, homocysteine or acetyl phenyalanine;

R.sup.2 is NH.sub.2 or OH;

[0092] Z.sup.1 is absent or has the sequence:

TABLE-US-00014 GlyProSerSerGlyAlaProProProSer; GlyProSerSerGlyAlaProProProSerCys; LysArgAsnArgAsnAsnIleAla; or LysArgAsnArg;

Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met, Har, Dbu, Dpr and Orn; wherein, if Z.sup.1 is absent, the compound has a substitution or deletion relative to human glucagon at one or more of positions X1, X2, X3, X10, X12, X15, X16, X17, X18, X20, X21, X23, X24, X27, X28 and X29; or a pharmaceutically acceptable salt or derivative thereof; wherein said compound has higher GLP-1 receptor selectivity than human glucagon and/or wherein the compound exhibits at least 20% of the activity of native GLP-1 at the GLP-1 receptor.

[0093] In addition, in certain embodiments, X may differ from Formula VII by 1 to 3 amino acid modifications at positions selected from 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, 24, 27, 28 and 29.

[0094] Compounds having sequences according to Formula VII are described in WO2008/101017.

[0095] X may have the Formula VII.2:

TABLE-US-00015 (SEQ ID NO: 52) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu- Asp-X16-X17-Arg-Ala-Gln-Asp-Phe-Val-Gln- Trp-Leu-X27-Asn-Thr (Compound 52)

wherein X16 is Glu, Gln, homoglutamic acid or homocysteic acid; X17 is Arg, Cys, Orn, homocysteine or acetyl phenylalanine;

X27 is Met, Leu or Nle

[0096] X may have the Formula VII.3:

TABLE-US-00016 (SEQ ID NO: 53) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-X16-Arg-Arg-Ala-Gln-X21-Phe-Val-Gln- Trp-Leu-X27-Asn-Thr (Compound 53)

wherein X16 is Glu, Gln, homoglutamic acid or homocysteic acid; X21 is Asp, Cys, Orn, homocysteine or acetyl phenylalanine;

X27 is Met, Leu or Nle;

[0097] X may have the Formula VII.4:

TABLE-US-00017 (SEQ ID NO: 54) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-X16-Arg-Arg-Al- a-Gln-X21-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr (Compound 54)

wherein X16 is Glu, Gln, homoglutamic acid or homocysteic acid; X24 is Gln, Cys, Orn, homocysteine or acetyl phenylalanine;

X27 is Met, Leu or Nle.

[0098] X may have the Formula VII.5:

TABLE-US-00018 (SEQ ID NO: 55) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-X16-Arg-Arg-Al- a-Gln-X21-Phe- Val-X24-Trp-Leu-X27-Asn-Thr (Compound 55)

wherein X16 is Glu, Gln, homoglutamic acid or homocysteic acid; X21 is Asp, Cys, Orn, homocysteine or acetyl phenylalanine; X24 is Gln, Cys, Orn, homocysteine or acetyl phenylalanine;

X27 is Met, Leu or Nle.

[0099] X may have the Formula VII.6:

TABLE-US-00019 (SEQ ID NO: 56) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-X21-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr (Compound 56)

wherein X21 is Asp, Cys, Orn, homocysteine or acetyl phenylalanine;

X27 is Met, Leu or Nle.

[0100] X may have the Formula VII.7:

TABLE-US-00020 (SEQ ID NO: 57) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Asp-Phe- Val-X24-Trp-Leu-X27-Asn-Thr (Compound 57)

wherein X24 is Gln, Cys, Orn, homocysteine or acetyl phenylalanine;

X27 is Met, Leu or Nle.

[0101] X may have the Formula VII.8:

TABLE-US-00021 (SEQ ID NO: 58) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-X16-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Gln-Trp-Leu-Met-Asn-Thr (Compound 58)

wherein X16 is Glu, Gln, homoglutamic acid or homocysteic acid.

[0102] X may have the Formula VII.9:

TABLE-US-00022 (SEQ ID NO: 59) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr (Compound 59)

wherein

X27 is Met, Leu or Nle.

[0103] X may have the Formula VII.19:

TABLE-US-00023 (SEQ ID NO: 60) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Glu-Trp-Leu-Met-Asn-Thr-X30 (Compound 60)

wherein X30 is any suitable amino acid.

[0104] X may have the Formula VII.20:

TABLE-US-00024 (SEQ ID NO: 61) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-X16-Arg-Arg-Al- a-X20-Asp-Phe- Val-X24-Trp-Leu-Met-X28-X29 (Compound 61)

wherein X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln, Lys, Arg, Orn or Citrulline;

X24 is Gln or Glu;

X28 is Asn, Asp or Lys;

X29 is Thr or Gly.

[0105] X may have the Formula VII.21:

TABLE-US-00025 (SEQ ID NO: 62) His-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala- -Gln-Asp-Phe- Val-Gln-Trp-Leu-Met-Asn-Thr (Compound 62)

wherein X2 is D-Ser, Ala, Gly, N-methyl Ser or aminoisobutyric acid.

[0106] X may have the Formula VII.22:

TABLE-US-00026 (SEQ ID NO: 63) His-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala- -Gln-Asp-Phe- Val-Gln-Trp-Leu-Met-Asn-Thr (Compound 63)

wherein X2 is aminoisobutyric acid.

[0107] X may have the Formula VII.23:

TABLE-US-00027 (SEQ ID NO: 64) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Cys-Arg-Al- a-Gln-Asp-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr (Compound 64)

wherein the Cys at position 17 is PEGylated;

X27 is Met, Leu or Nle.

[0108] X may have the Formula VII.24:

TABLE-US-00028 (SEQ ID NO: 65) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Cys-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr (Compound 65)

wherein the Cys at position 21 is PEGylated;

X27 is Met, Leu or Nle.

[0109] X may have the Formula VII.25:

TABLE-US-00029 (SEQ ID NO: 66) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Cys-Trp-Leu-X27-Asn-Thr (Compound 66)

wherein the Cys at position 24 is PEGylated;

X27 is Met, Leu or Nle.

[0110] X may have the Formula VII.30:

TABLE-US-00030 (SEQ ID NO: 67) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (Compound 67)

wherein

X27 is Met, Leu or Nle.

[0111] X may have the Formula VII.31:

TABLE-US-00031 (SEQ ID NO: 68) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Gln-Trp-Leu-X27-Asn-Thr-Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala (Compound 68)

wherein

X27 is Met, Leu or Nle.

[0112] X may have the Formula VII.32:

TABLE-US-00032 (Compound 69) (SEQ ID NO: 69) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg- Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-X27-Asn-Thr-Lys-Arg-Asn-Arg

wherein

X27 is Met, Leu or Nle.

[0113] X may have the Formula VII.33:

TABLE-US-00033 (Compound 70) (SEQ ID NO: 70) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-X15- X16-Arg-Arg-Ala-X20-Asp-Phe-Val-X24-Trp-Leu-Met-X28-X29

wherein X15 is Asp, Glu, homoglutamic acid, cysteic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln or Lys;

X24 is Gln or Glu;

[0114] X28 is Asn, Lys or an acidic amino acid; X29 is Thr, Gly or an acidic amino acid.

[0115] X may have the Formula VII.36:

TABLE-US-00034 (Compound 71) (SEQ ID NO: 71) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser.

[0116] X may have the Formula VII.37:

TABLE-US-00035 (SEQ ID NO: 72) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Al- a-Gln-Asp-Phe- Val-Cys-Trp-Leu-Met-Asn-Thr (Compound 72)

wherein 24 2-butyrolactone is bound through thiol group of Cys.

[0117] X may have the Formula VII.38:

TABLE-US-00036 (Compound 73) (SEQ ID NO: 73) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Cys-Trp-Leu-Met-Asn-Thr

wherein a 24 carboxymethyl group is bound through thiol group of Cys.

[0118] X may have the Formula VII.39:

TABLE-US-00037 (Compound 74) (SEQ ID NO: 74) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Arg-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly- Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser.

[0119] X may have the Formula VII.40:

TABLE-US-00038 (Compound 75) (SEQ ID NO: 75) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-X15- Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-X28-Thr

wherein

X15 is Glu or Asp;

X28 is Glu or Asp.

[0120] X may have the Formula VII.41:

TABLE-US-00039 (Compound 76) (SEQ ID NO: 76) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-X15- Glu-Arg-Arg-Ala-Asp-Phe-Val-Gln-Trp-Leu-Met-X28-Thr

wherein

X15 is Glu or Asp;

X28 is Glu or Asp; and

[0121] a lactam ring is present between the side chains at positions 12 and 16.

[0122] X may have the Formula VII.42:

TABLE-US-00040 (Compound 77) (SEQ ID NO: 77) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-X15- Glu-Arg-Arg-Ala-Lys-Asp-Phe-Val-Gln-Trp-Leu-Met-X28-Thr

wherein

X15 is Glu or Asp;

X28 is Glu or Asp; and

[0123] a lactam ring is present between the side chains at positions 16 and 20.

[0124] X may have the Formula VII.43:

TABLE-US-00041 (Compound 78) (SEQ ID NO: 78) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-X15- Ser-Arg-Arg-Ala-Lys-Asp-Phe-Val-Glu-Trp-Leu-Met-X28-Thr

wherein

X15 is Glu or Asp;

X28 is Glu or Asp; and

[0125] a lactam ring is present between side chains at positions 20 and 24.

[0126] X may have the Formula VII.44:

TABLE-US-00042 (Compound 79) (SEQ ID NO: 79) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-X15- Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Glu-Trp-Leu-Met-Lys-X29

wherein

X15 is Glu or Asp;

X29 is Glu or Thr.

[0127] In the above Formulae Z1 and Z2 are typically absent. The C-terminus of the compound may be amidated (R.sup.2.dbd.NH.sub.2).

[0128] X may have the Formula VII.45:

TABLE-US-00043 (Compound 80) (SEQ ID NO: 80) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-X12-Tyr-Leu-X15- X16-Arg-Arg-Ala-X20-Asp-Phe-Val-X24-Trp-Leu-Met-X28-X29

wherein

X12 is Lys or Glu;

[0129] X15 is Asp, Glu, homoglutamic acid, cysteic acid or homocysteic acid; X16 is Ser, Gln, Glu, Lys, homoglutamic acid, cysteic acid or homocysteic acid;

X20 is Gln, Glu or Lys;

X24 is Gln, Lys or Glu;

[0130] X28 is Asn, Lys or an acidic amino acid; X29 is Thr, Gly or an acidic amino acid.

[0131] X may have the Formula VII.46:

TABLE-US-00044 (Compound 81) (SEQ ID NO: 81) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- X16-Arg-Arg-Ala-X20-Asp-Phe-Val-X24-Trp-Leu-Met-Asn-Thr

wherein X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln or Lys;

X24 is Gln or Glu.

[0132] X may have the Formula VII.47:

TABLE-US-00045 (Compound 82) (SEQ ID NO: 82) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Glu-Arg-Arg-Ala-Lys-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr.

[0133] X may have the Formula VII.48:

TABLE-US-00046 (Compound 83) (SEQ ID NO: 83) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Lys-Asp-Phe-Val-Glu-Trp-Leu-Met-Asn-Thr.

[0134] X may have the Formula VII.49:

TABLE-US-00047 (Compound 84) (SEQ ID NO: 84) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Glu-Trp-Leu-Met-Asn-Thr.

[0135] X may have the Formula VII.50:

TABLE-US-00048 (SEQ ID NO: 85) His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser- Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala- Trp-Leu-Val-Lys-Gly-Arg-Gly (Compound 85)

[0136] X may have the Formula VII.51:

TABLE-US-00049 (SEQ ID NO: 86) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-X15-X16-Arg-Arg-Ala-X20-X21-Phe-Val-X24- Trp-Leu-Met-X28-X29 (Compound 86)

wherein X15 is Asp, Glu, homoglutamic acid, cysteic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln, Lys, Arg, Orn or Citrulline;

[0137] X21 is Asp, Glu, homoglutamic acid or homocysteic acid;

X24 is Gln or Glu;

[0138] X28 is Asn, Lys or an acidic amino acid; X29 is Thr, Gly or an acidic amino acid.

[0139] X may have the Formula VII.52:

TABLE-US-00050 (SEQ ID NO: 87) His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser- Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala- Trp-Leu-Val-Lys-Gly-Arg. (Compound 87)

[0140] X may have the Formula VII.53:

TABLE-US-00051 (SEQ ID NO: 88) His-Ser-X3-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-X15-X16-Arg-Arg-Ala-X20-Asp-Phe-Val-X24- Trp-Leu-Met-X28-X29 (Compound 88)

wherein

X3 is Glu, Orn or Nle;

[0141] X15 is Asp, Glu, homoglutamic acid, cysteic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln or Lys;

X24 is Gln or Glu;

[0142] X28 is Asn, Lys or an acidic amino acid; X29 is Thr or an acidic amino acid.

[0143] X may have the Formula VII.54:

TABLE-US-00052 (SEQ ID NO: 89) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-Glu-X17-X18-Ala-Lys-X21-Phe-X23-X24- Trp-Leu-Met-Asn-Thr (Compound 89)

wherein

X17 is Arg or Gln;

X18 is Arg or Ala;

X21 is Asp or Glu;

X23 is Val or Ile;

X24 is Gln or Ala.

[0144] X may have the Formula VII.56:

TABLE-US-00053 (SEQ ID NO: 90) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-X15-X16-Arg-Arg-Ala-X20-X21-Phe-X23-X24-Trp- Leu-X27-X28-X29 (Compound 90)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, Acetyl-His, homo-His, DMIA, N-methyl His, Alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, Aib or N-methyl Ala;

X3 is Gln, Glu, Orn or Nle

[0145] X15 is Asp, Glu, cysteic acid, homoglutamic acid homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid, or homocysteic acid;

X20 is Gln, Lys, Arg, Orn or Citrulline;

[0146] X21 is Gln, Glu, Asp, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val or Ile;

[0147] X24 is Ala, Gln, Glu, Cys, Orn, homocysteine or acetyl phenyalanine;

X27 is Met, Leu or Nle;

X28 is Asn, Lys or Asp;

[0148] X29 is Thr, Gly Lys, Cys, Orn, homocysteine or acetyl phenyalanine.

[0149] X may have the Formula VII.57:

TABLE-US-00054 (SEQ ID NO: 91) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-X15-Glu-Arg-Arg-Ala-X20-X21-Phe-X23-X24-Trp- Leu-X27-X28-X29 (Compound 91)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, Acetyl-His, homo-His, DMIA, N-methyl His, Alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, Aib or N-methyl Ala;

X3 is Gln, Glu, Orn or Nle;

[0150] X15 is Asp, Glu, Cysteic acid, homoglutamic acid or homocysteic acid;

X20 is Gln, Lys, Arg, Orn, or Citrulline;

[0151] X21 is Gln, Glu, Asp, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val or Ile;

[0152] X24 is Ala, Gln, Glu, Cys, Orn, homocysteine or acetyl phenyalanine;

X27 is Met, Leu or Nle;

X28 is Asn, Lys or Asp;

[0153] X29 is Thr, Gly, Cys, Orn, homocysteine or acetyl phenyalanine; and wherein a lactam bridge is present between side chains at positions 12 and 16.

[0154] X may have the Formula VII.58:

TABLE-US-00055 (SEQ ID NO: 92) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-X15-Glu-Arg-Arg-Ala-Lys-X21-Phe-X23-X24-Trp- Leu-X27-X28-X29 (Compound 92)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, Acetyl-His, homo-His, DMIA, N-methyl His, Alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, Aib or N-methyl Ala;

X3 is Gln, Glu, Orn or Nle;

[0155] X15 is Asp, Glu, Cysteic acid, homoglutamic acid or homocysteic acid; X21 is Gln, Glu, Asp, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val or Ile;

[0156] X24 is Ala, Gln, Glu, Cys, Orn, homocysteine or acetyl phenyalanine,

X27 is Met, Leu or Nle;

X28 is Asn, Lys or Asp;

[0157] X29 is Thr, Gly, Cys, Orn, homocysteine or acetyl phenyalanine; and wherein a lactam bridge is present between side chains at positions 16 and 20.

[0158] X may have the Formula VII.59:

TABLE-US-00056 (SEQ ID NO: 93) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-X15-X16-Arg-Arg-Ala-Lys-X21-Phe-X23-Glu-Trp- Leu-X27-X28-X29 (Compound 93)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, Acetyl-His, homo-His, DMIA, N-methyl His, Alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, Aib or N-methyl Ala;

X3 is Gln, Glu, Orn or Nle;

[0159] X15 is Asp, Glu, Cysteic acid, homoglutamic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid; X21 is Gln, Glu, Asp, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val or Ile;

X27 is Met, Leu or Nle;

X28 is Asn, Lys or Asp;

[0160] X29 is Thr, Gly, Cys, Orn, homocysteine or acetyl phenyalanine; and wherein a lactam bridge is present between side chains at positions 20 and 24.

[0161] X may have the Formula VII.60:

TABLE-US-00057 (SEQ ID NO: 94) X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-X15-X16-Arg-Arg-Ala-X20-X21-Phe-X23-Glu-Trp- Leu-X27-Lys-X29 (Compound 94)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, Acetyl-His, homo-His, DMIA, N-methyl His, Alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, Aib or N-methyl Ala;

X3 is Gln, Glu, Orn or Nle;

[0162] X15 is Asp, Glu, Cysteic acid, homoglutamic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln, Lys, Arg, Orn or Citrulline

[0163] X21 is Gln, Glu, Asp, Cys, Orn, homocysteine or acetyl phenyalanine;

X23 is Val or Ile;

X27 is Met, Leu or Nle;

[0164] X29 is Thr, Gly, Cys, Orn, homocysteine or acetyl phenyalanine; and wherein a lactam bridge is present between side chains at positions 24 and 28

[0165] X--Z.sup.1 may have the Formula VII.61:

TABLE-US-00058 (SEQ ID NO: 95) X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-Asp-Glu-Arg-X18-Ala-Lys-Asp-Phe-Val-X24-Trp- Leu-Met-Asn-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-Cys (Corn pound 95)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, acetyl-His, homo-His, DMIA, N-methyl His, alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, Val, Gly, N-methyl Ser, Aib, N-methyl Ala or D-Ala;

X18 is Ala or Arg;

X24 is Ala, Gln or Cys-PEG;

X29 is Thr-CONH2, Cys-PEG, or Gly;

[0166] position 40 is Cys-PEG or not present; provided that positions 30 to 40 (Z.sup.2) are present only if position 29 is Gly.

[0167] X--Z.sup.1 may have the Formula VII.62:

TABLE-US-00059 (SEQ ID NO: 96) X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr- Leu-Asp-Glu-Gln-X18-Ala-Lys-Glu-Phe-Ile-X24-Trp- Leu-Met-Asn-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-Cys (Compound 96)

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, acetyl-His, homo-His, DMIA, N-methyl His, alpha-methyl His, or imidazole acetic acid;

X2 is Ser, D-Ser, Ala, Val, Gly, N-methyl Ser, Aib, N-methyl Ala or D-Ala;

X18 is Ala or Arg;

X24 is Ala, Gln or Cys-PEG;

X29 is Thr-CONH2, Cys-PEG, or Gly;

[0168] position 40 is Cys-PEG or not present; provided that positions 30 to 40 (Z.sup.2) are present only if position 29 is Gly

[0169] X may have the Formula VII.63:

TABLE-US-00060 (SEQ ID NO: 97) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-Asp-X16-Arg-Arg-Ala-X20-X21-Phe-Val-X24- Trp-Leu-X27-Asp-Thr (Compound 97)

wherein X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln or Lys;

[0170] X21 is Asp, Lys, Cys, Orn, homocysteine or acetyl phenyalanine; X24 is Gln, Lys, Cys, Orn, homocysteine or acetylphenyalanine;

X27 is Met, Leu or Nle.

[0171] X--Z.sup.1 may have the Formula VII.64:

TABLE-US-00061 (SEQ ID NO: 98) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu-X15-X16-Arg-Arg-Ala-X20-Asp-Phe-Val-X24- Trp-Leu-Met-X28-Gly-Gly-Pro-Ser-Ser-Gly-Pro-Pro- Pro-Ser (Compound 98)

wherein X15 is Asp, Glu, homoglutamic acid, cysteic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid;

X20 is Gln or Lys;

X24) is Gln or Glu;

X28 is Asn, Lys or Asp.

[0172] X may have the Formula VII.66:

TABLE-US-00062 (SEQ ID NO: 99) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys- Tyr-Leu- Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln- Trp-Leu-Met-X28-X29 (Compound 99)

wherein

X28 is Asp or Asn;

X29 is Thr or Gly;

[0173] and wherein a lactam ring is present between side chains at positions 12 and 16.

[0174] X may have the Formula VII.67:

TABLE-US-00063 (Compound 100) (SEQ ID NO: 100) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Glu-Arg-Arg-Ala-Lys-Asp-Phe-Val-Gln-Trp-Leu-Met-X28-X29

wherein

X28 is Asp or Asn;

X29 is Thr or Gly;

[0175] and wherein a lactam ring is present between side chains at positions 16 and 20.

[0176] X may have the Formula VII.68:

TABLE-US-00064 (Compound 101) (SEQ ID NO: 101) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Lys-Asp-Phe-Val-Glu-Trp-Leu-Met-X28-X29

wherein

X28 is Asp or Asn;

X29 is Thr or Gly;

[0177] and wherein a lactam ring is present between side chains at positions 20 and 24.

[0178] X may have the Formula VII.69:

TABLE-US-00065 (Compound 102) (SEQ ID NO: 102) His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Glu-Trp-Leu-Met-Lys-X29

wherein

X29 is Thr or Gly;

[0179] and wherein a lactam ring is present between side chains at positions 24 and 28.

[0180] Further specific compounds which may be useful in the methods of the invention are shown in FIG. 3: Table 2 (SEQ ID NOs: 344-797) and Table 3 (SEQ ID NOs: 264-338)

DESCRIPTION OF THE FIGURES

[0181] FIG. 1: Effects of vehicle, glucagon, and a glucagon-GLP1 dual-agonist (Compound 12) on A: Heart rate in insulin-resistant (IR) JCR: LA rat hearts; B: Cardiac output in IR hearts; C: Cardiac power in IR hearts. Values are presented as mean+SEM. * P<0.05; ** P<0.01 compared to baseline.

[0182] FIG. 2: Energy state in hearts from insulin-resistant (IR) JCR: LA rats after perfusion with increasing concentrations of vehicle (n=4), glucagon (n=6), and a glucagon-GLP1 dual-agonist (Compound 12) (n=5). A: Adenosine monophosphate (AMP) concentrations. B: Adenosine diphosphate (ADP) concentrations. C: Adenosine triphosphate (ATP) concentrations. D: ATP/AMP ratios. E: ATP/ADP ratios. Values are presented as mean+SEM. * P<0.05; ** P<0.01 compared to vehicle.

[0183] FIG. 3: Shows a table (Table 2) of compounds by sequence (SEQ ID NOs: 344-797) which may be useful in accordance with the invention.

[0184] FIG. 4: Strokework calculated from individual data for each compound infused with compound 1 or glucagon-GLP-1 dual agonists. Dose is given in nmol/kg/min and indicated on top of each figure. A maximum of 40% increase in strokework was set as end point, after which infusion was discontinued.

[0185] FIG. 5: Heart rate calculated from individual data for each compound infused with compound 1 or glucagon-GLP-1 dual agonists. Dose is given in nmol/kg/min and indicated on top of each figure. A maximum of 40% increase in strokework (FIG. 4) was set as end point, after which infusion was discontinued.

[0186] FIG. 6: Shows a table (Table 3) of compounds by sequence (SEQ ID NOs: 264-338) which may be useful in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0187] Throughout this specification, the conventional one letter and three letter codes for naturally occurring amino acids are used, as well as generally accepted three letter codes for other amino acids, such as Aib (.alpha.-aminoisobutyric acid), Orn (ornithine), Dbu (2,4-diaminobutyric acid) and

[0188] Dpr (2,3-diaminopropanoic acid), Cit (citrulline), 1 NaI (1-naphthylalanine), Hph (homophenylalanine), Hse (homoserine) and Orn (ornithine).

[0189] In the context of the present invention, C.sub.1-6alkyl and C.sub.1-4 alkyl include methyl, ethyl, 1-propyl and 2-propyl.

[0190] In the context of the present invention, the expression "positive inotropic" refers to agents that increase the force and velocity of myocardial contractility, i.e. improves myocardial contractility.

[0191] The term "native glucagon" refers to native human glucagon having the sequence H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg- -Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-OH.

[0192] The terms "oxyntomodulin" and "OXM" refer to native human oxyntomodulin having the sequence H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg- -Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys-Arg-Asn-Arg-Asn-Asn-Ile-A- la-OH.

[0193] In certain embodiments of compounds of the invention wherein the amino acid residue X3 is 3-(heterocyclyl)alanyl [i.e. an amino acid residue deriving from a 3-(heterocyclyl)-substituted alanine], then X3 may be selected from the group consisting of 3-(2-furyl)alanyl, 3-(4-thiazolyl)alanyl, 3-(3-pyridyl)alanyl, 3-(4-pyridyl)alanyl, 3-(1-pyrazolyl)alanyl, 3-(2-thienyl)alanyl, 3-(3-thienyl)alanyl and 3-(1,2,4-triazol-1-yl)alanyl.

Peptide Sequence X

[0194] For the avoidance of doubt, in the definitions above, it is generally intended that the sequence of X only differs from the formulae shown at those positions which are stated to allow variation. Amino acids within the sequences X described herein can be considered to be numbered consecutively from 1 to 29 in the conventional N-terminal to C-terminal direction. Reference to a "position" within X should be construed accordingly, as should reference to positions within native human glucagon and other molecules.

[0195] In any of the formulae provided herein, the residue at position X3 may alternatively be selected from acetamidomethyl-cysteine, acetyldiaminobutanoic acid, carbamoyldiaminopropanoic acid, methylglutamine and methionine sulfoxide.

[0196] Certain formulae presented above allow the residues at positions X27, X28 and/or X29 to be absent. Typically, if X28 is absent, then X29 is also absent. If X27 is absent, then X28 and X28 are both also absent. In other words, X28 will not be absent if X29 is present, and X27 will not be absent if either of X28 and X29 is present.

[0197] When Z.sup.1 is absent, the peptide sequence X can be considered an analogue of glucagon. In such embodiments, the peptide sequence X differs from the sequence of native human glucagon at one or more of the 29 positions, for example at a minimum of 2 of 29 positions, e.g. at a minimum of 3, 4, 5, 6 of 29 positions.

[0198] In certain embodiments, when X differs from human glucagon at only one position, that position may be X12, X17 or X18.

[0199] The residue at X12 may be Ala or Arg.

[0200] The residue at X17 may be Glu or Lys.

[0201] The residue at X18 may be His, Ser, Ala or Tyr.

[0202] Thus the peptide X may have the sequence:

TABLE-US-00066 (Compound 103) (SEQ ID NO: 103) HSQGTFTSDYSAYLDSRRAQDFVQWLMNT; (Compound 104) (SEQ ID NO: 104) HSQGTFTSDYSRYLDSRRAQDFVQWLMNT; (Compound 106) (SEQ ID NO: 106) HSQGTFTSDYSKYLDSERAQDFVQWLMNT; (Compound 107) (SEQ ID NO: 107) HSQGTFTSDYSKYLDSKRAQDFVQWLMNT; (Compound 108) (SEQ ID NO: 108) HSQGTFTSDYSKYLDSRHAQDFVQWLMNT; (Compound 109) (SEQ ID NO: 109) HSQGTFTSDYSKYLDSRSAQDFVQWLMNT; (Compound 110) (SEQ ID NO: 110) HSQGTFTSDYSKYLDSRAAQDFVQWLMNT; or (Compound 111) (SEQ ID NO: 111) HSQGTFTSDYSKYLDSRYAQDFVQWLMNT.

[0203] Sequences having 2 or 3 differences from human glucagon include:

TABLE-US-00067 (Compound 112) (SEQ ID NO: 112) HSQGTFTSDYSRYLDSRRAKDFVQWLLNT; (Compound 113) (SEQ ID NO: 113) HSQGTFTSDYSRYLDSRRAQDFVQWLLNT; (Compound 114) (SEQ ID NO: 114) HSQGTFTSDYSRYLDSRRAQDFVQWLLNK; (Compound 115) (SEQ ID NO: 115) HSQGTFTSDYSKYLDSALAQDFVQWLLNT; (Compound 116) (SEQ ID NO: 116) HSQGTFTSDYSKYLDKRRAEDFVQWLMNT; (Compound 117) (SEQ ID NO: 117) HSQGTFTSDYSKYLDK( )RRAE( )DFVQWLMNT; (Compound 118) (SEQ ID NO: 118) HSQGTFTSDYSRYLDERRAQDFVQWLMNT; (Compound 119) (SEQ ID NO: 119) HSQGTFTSDYSK( )YLDE( )RRAQDFVQWLMNT; (Compound 120) (SEQ ID NO: 120) HSQGTFTSDYSKYLDSRRAQDFIEWLMNT; and (Compound 121) (SEQ ID NO: 121) HSQGTFTSDYSKYLDSKAAQDFVQWLMNT; (Compound 122) (SEQ ID NO: 122) HSQGTFTSDYSKYLDSLAAQDFVQWLLNT.

[0204] Whether Z.sup.1 is present or absent, it may be desirable that the peptide sequence X differs from human glucagon at a maximum of 10 of 29 positions, e.g. at a maximum of 7, 8, 9 or 10 positions.

Z.sup.1

[0205] Z.sup.1 may have the sequence:

GlyProSerSerGlyAlaProProProSer, representing the C-terminal 10 amino acids of native Exendin-4; GlyProSerSerGlyAlaProProProSerCys, representing the C-terminal 10 amino acids of native Exendin-4 plus an additional C-terminal Cys residue; LysArgAsnArgAsnAsnIleAla, representing the C-terminal 8 amino acids of native oxyntomodulin; or

LysArgAsnArg.

Z.sup.2

[0206] The compound may comprise a C-terminal peptide sequence Z.sup.2 of 1-20 amino acids, for example to stabilise the conformation and/or secondary structure of the glucagon analogue peptide, and/or to make the glucagon analogue peptide more resistant to enzymatic hydrolysis, e.g. as described in WO99/46283.

[0207] When present, Z.sup.2 represents a peptide sequence of 1-20 amino acid residues, e.g. in the range of 1-15, more preferably in the range of 1-10 in particular in the range of 1-7 amino acid residues, e.g., 1, 2, 3, 4, 5, 6 or 7 amino acid residues, such as 6 amino acid residues. Each of the amino acid residues in the peptide sequence Z.sup.2 may independently be selected from Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu (2,4 diaminobutyric acid), Dpr (2,3-diaminopropanoic acid) and Orn (ornithine). Preferably, the amino acid residues are selected from Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn, more preferably may be selected exclusively from Glu, Lys, and Cys, especially Lys. The above-mentioned amino acids may have either D- or L-configuration, but preferably have an L-configuration. Particularly preferred sequences for Z.sup.2 are sequences of four, five, six or seven consecutive lysine residues (i.e. Lys.sub.3, Lys.sub.4, Lys.sub.5, Lys.sub.6 or Lys.sub.7), and particularly five or six consecutive lysine residues. Other exemplary sequences of Z are shown in WO 01/04156, the content of which is incorporated herein by reference. Alternatively the C-terminal residue of the sequence Z.sup.2 may be a Cys residue. This may assist in modification of the compound, e.g. conjugation to a lipophilic substituent or polymeric moiety as described below. In such embodiments, the sequence Z.sup.2 may, for example, be only one amino acid in length (i.e. Z.sup.2=Cys) or may be two, three, four, five, six or even more amino acids in length. The other amino acids therefore serve as a spacer between the peptide X and the terminal Cys residue. In such embodiments, Z.sup.1 may be absent.

[0208] In some embodiments, the peptide sequence Z.sup.2 has no more than 25% amino acid sequence identity with the corresponding sequence of the IP-1 portion of human OXM (which has the sequence Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala).

[0209] "Percent (%) amino acid sequence identity" of a given peptide or polypeptide sequence with respect to another polypeptide sequence (e.g. IP-1) is calculated as the percentage of amino acid residues in the given peptide sequence that are identical with corresponding amino acid residues in the corresponding sequence of that other polypeptide when the two are aligned with one another, introducing gaps for optimal alignment if necessary. % identity values may be determined by WU-BLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)). WU-BLAST-2 uses several search parameters, most of which are set to the default values. The adjustable parameters are set with the following values: overlap span=1, overlap fraction=0.125, word threshold (T)=11. A % amino acid sequence identity value is determined by the number of matching identical residues as determined by WU-BLAST-2, divided by the total number of residues of the reference sequence (gaps introduced by WU-BLAST-2 into the reference sequence to maximize the alignment score being ignored), multiplied by 100.

[0210] Thus, when Z.sup.2 is aligned optimally with the 8 amino acids of IP-1, it has no more than two amino acids which are identical with the corresponding amino acids of IP-1.

Amino Acid Modification

[0211] One or more of the amino acid side chains in any of the compounds suitable for use in the present invention may be conjugated to a lipophilic substituent. The lipophilic substituent may be covalently bonded to an atom in the amino acid side chain, or alternatively may be conjugated to the amino acid side chain by a spacer. The amino acid may be part of the peptide X, or part of the peptides Z.sup.1 or Z.sup.2. The spacer, when present, is used to provide a spacing between the rest of the compound and the lipophilic substituent.

[0212] Without wishing to be bound by theory, it is thought that the lipophilic substituent binds albumin in the blood stream, thus shielding the compounds of the invention from enzymatic degradation which can enhance the half-life of the compounds. Thus compound modified in this way may be particularly suitable for chronic treatment.

[0213] The lipophilic substituent may be attached to the amino acid side chain or to the spacer via an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide. Accordingly it will be understood that preferably the lipophilic substituent includes an acyl group, a sulphonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulphonyl ester, thioester, amide or sulphonamide. Preferably, an acyl group in the lipophilic substituent forms part of an amide or ester with the amino acid side chain or the spacer.

[0214] The lipophilic substituent may include a hydrocarbon chain having 4 to 30 C atoms. Preferably it has at least 8 or 12 C atoms, and preferably it has 24 C atoms or fewer, or 20 C atoms or fewer. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. It will be understood that the hydrocarbon chain is preferably substituted with a moiety which forms part of the attachment to the amino acid side chain or the spacer, for example an acyl group, a sulphonyl group, an N atom, an O atom or an S atom. Most preferably the hydrocarbon chain is substituted with acyl, and accordingly the hydrocarbon chain may be part of an alkanoyl group, for example palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

[0215] In certain embodiments, the lipophilic substituent may include a hydrocarbon chain having 10 to 24 C atoms, e.g. 10 to 22 C atoms, e.g. 10 to 20 C atoms. Preferably it has at least 11 C atoms, and preferably it has 18 C atoms or fewer. For example, the hydrocarbon chain may contain 12, 13, 14, 15, 16, 17 or 18 carbon atoms. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. From the discussion above it will be understood that the hydrocarbon chain is preferably substituted with a moiety which forms part of the attachment to the amino acid side chain or the spacer, for example an acyl group, a sulphonyl group, an N atom, an O atom or an S atom. Most preferably the hydrocarbon chain is substituted with acyl, and accordingly the hydrocarbon chain may be part of an alkanoyl group, for example a dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl or eicosanoyl group.

[0216] Accordingly, the lipophilic substituent may have the formula shown below:

##STR00001##

[0217] A may be, for example, an acyl group, a sulphonyl group, NH, N-alkyl, an O atom or an S atom, preferably acyl. n is an integer from 3 to 29, preferably at least 7 or at least 11, and preferably 23 or less, more preferably 19 or less.

[0218] The hydrocarbon chain may be further substituted. For example, it may be further substituted with up to three substituents selected from NH.sub.2, OH and COOH. If the hydrocarbon chain is further substituted, preferably it is further substituted with only one substituent. Alternatively or additionally, the hydrocarbon chain may include a cycloalkane or heterocycloalkane, for example as shown below:

##STR00002##

[0219] Preferably the cycloalkane or heterocycloalkane is a six-membered ring. Most preferably, it is piperidine.

[0220] Alternatively, the lipophilic substituent may be based on a cyclopentanophenanthrene skeleton, which may be partially or fully unsaturated, or saturated. The carbon atoms in the skeleton each may be substituted with Me or OH. For example, the lipophilic substituent may be cholyl, deoxycholyl or lithocholyl.

[0221] As mentioned above, the lipophilic substituent may be conjugated to the amino acid side chain by a spacer. When present, the spacer is attached to the lipophilic substituent and to the amino acid side chain. The spacer may be attached to the lipophilic substituent and to the amino acid side chain independently by an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide. Accordingly, it may include two moieties independently selected from acyl, sulphonyl, an N atom, an O atom or an S atom. The spacer may have the formula:

##STR00003##

wherein B and D are each independently selected from acyl, sulphonyl, NH, N-alkyl, an O atom or an S atom, preferably from acyl and NH. Preferably, n is an integer from 1 to 10, preferably from 1 to 5. The spacer may be further substituted with one or more substituents selected from C.sub.1-6 alkyl, amino-C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl and carboxyl.sub.1-6 alkyl.

[0222] Alternatively, the spacer may have two or more repeat units of the formula above. B, D and n are each selected independently for each repeat unit. Adjacent repeat units may be covalently attached to each other via their respective B and D moieties. For example, the B and D moieties of the adjacent repeat units may together form an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide. The free B and D units at each end of the spacer are attached to the amino acid side chain and the lipophilic substituent as described above.

[0223] Preferably the spacer has five or fewer, four or fewer or three or fewer repeat units. Most preferably the spacer has two repeat units, or is a single unit.

[0224] The spacer (or one or more of the repeat units of the spacer, if it has repeat units) may be, for example, a natural or unnatural amino acid. It will be understood that for amino acids having functionalised side chains, B and/or D may be a moiety within the side chain of the amino acid. The spacer may be any naturally occurring or unnatural amino acid. For example, the spacer (or one or more of the repeat units of the spacer, if it has repeat units) may be Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, Glu, .gamma.-Glu, .epsilon.-Lys, Asp, Ser, Thr, Gaba, Aib, .beta.-Ala (i.e. 3-aminopropanoyl), 4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl or 8-amino-3,6-dioxaoctanoyl. In certain embodiments, the spacer is a residue of Glu, .gamma.-Glu, .epsilon.-Lys, .beta.-Ala (i.e. 3-aminopropanoyl), 4-aminobutanoyl, 8-aminooctanoyl or 8-amino-3,6-dioxaoctanoyl.

[0225] For example, the spacer may be a single amino acid selected from .gamma.-Glu, Gaba, .beta.-Ala and -Gly.

[0226] The lipophilic substituent may be conjugated to any amino acid side chain in the compound. Preferably, the amino acid side chain includes a carboxy, hydrox, thiol, amide or amine group, for forming an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide with the spacer or lipophilic substituent. For example, the lipophilic substituent may be conjugated to a side chain of a Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn residue, e.g. a side chain of a Glu, Lys, Ser, Cys, Dbu, Dpr or Orn residue. For example it may be a side chain of a Lys, Glu or Cys residue. Where two or more side chains carry a lipophilic substituent, they may be independently selected from these residues. Preferably, the lipophilic substituent is conjugated to Lys. However, any amino acid shown as Lys in the formulae provided herein may be replaced by Dbu, Dpr or Orn where a lipophilic substituent is added.

[0227] An example of a lipophilic substituent and spacer is shown in the formula below:

##STR00004##

[0228] Here, the side chain of a Lys residue from the peptide X is covalently attached to a .gamma.-Glu spacer via an amide linkage. A hexadecanoyl group is covalently attached to the .gamma.-Glu spacer via an amide linkage. This combination of lipophilic moiety and spacer, conjugated to a Lys residue, may be referred to by the short-hand notation K(Hexadecanoyl-.gamma.-Glu), e.g. when shown in formulae of specific compounds. .gamma.-Glu can also be referred to as isoGlu, and a hexadecanoyl group as a palmitoyl group. Thus it will be apparent that the notation (Hexadecanoyl-.gamma.-Glu) is equivalent to the notations (isoGlu(Palm)) or (isoGlu(Palmitoyl)) as used for example in PCT/GB2008/004121.

[0229] In certain embodiments, the side chain(s) of one or more of the residues at positions 16, 17, 18, 20, 24, 27, 28 or of Z.sup.2 are conjugated to a lipophilic substituent. For example, one side chain of such a residue may be conjugated to a lipophilic substituent. Alternatively, two, or even more than two, side chains of such residues may be conjugated to a lipophilic substituent.

[0230] In some embodiments, Z.sup.1 is absent and Z.sup.2 consists of only one amino acid residues, which can then be regarded as position 30. It may be preferable that position 30 is Cys or Lys.

[0231] For example, at least one of positions 16, 17, 18, 20 and 28 may be conjugated to a lipophilic substituent. In such cases, position 30 may be absent. When position 30 is present, it is typically conjugated to a lipophilic substituent.

[0232] Thus the compound may have just one lipophilic substituent, at position 16, 17, 18, 20, 24, 27, 28 or 30, preferably at position 16, 17 or 20, particularly at position 17.

[0233] Alternatively, the compound may have precisely two lipophilic substituents, each at one of positions 16, 17, 18, 20, 24, 27, 28 or 30. Preferably one or both lipophilic substituents are present at one of positions 16, 17 or 20.

[0234] Thus, the compound may have lipophilic substituents at positions 16 and 17, 16 and 18, 16 and 20, 16 and 24, 16 and 27, 16 and 28 or 16 and 30; at 17 and 18, 17 and 20, 17 and 24, 17 and 27, 17 and 28 or 17 and 30; at 18 and 20, 18 and 24, 18 and 27, 18 and 28 or 18 and 30; at 20 and 24, 20 and 27, 20 and 28 or 20 and 30; at 24 and 27, 24 and 28 or 24 and 30; at 27 and 28 or 27 and 30; or at 28 and 30.

[0235] In yet further embodiments, the compound may have one or more further lipophilic substituents (giving three or more in total) at further positions selected from positions 16, 17, 18, 20, 24, 27, 28 or 30. However it may be desirable that a maximum of two positions are derivatised in this way.

[0236] Certain combinations of lipophilic moiety and spacer are dodecanoyl-.gamma.-Glu, hexadecanoyl-.gamma.-Glu, hexadecanoyl-Glu, hexadecanoyl-[3-aminopropanoyl], hexadecanoyl-[8-aminooctanoyl], hexadecanoyl-.epsilon.-Lys, 2-butyloctanoyl-.gamma.-Glu, octadecanoyl-.gamma.-Glu and hexadecanoyl-[4-aminobutanoyl].

[0237] In certain embodiments, the peptide X may have the sequence:

TABLE-US-00068 (Compound 123) (SEQ ID NO: 123) HSQGTFTSDYSKYLDKKAAHDFVEWLLRA; (Compound 124) (SEQ ID NO: 124) HSQGTFTSDYSKYLDSKAAKDFVEWLLRA; (Compound 125) (SEQ ID NO: 125) HSQGTFTSDYSKYLDSKAAHDFVEWLKRA; (Compound 126) (SEQ ID NO: 126) HSQGTFTSDYSKYLDSKAAHDFVEWLLKA; (Compound 127) (SEQ ID NO: 127) HSQGTFTSDYSRYLDSKAAHDFVEWLLRA; (Compound 128) (SEQ ID NO: 128) HSQGTFTSDYSLYLDSKAAHDFVEWLLRA; (Compound 129) (SEQ ID NO: 129) HSQGTFTSDYSKYLDSKAAHDFVEWLLRAK; (Compound 130) (SEQ ID NO: 130) HSQGTFTSDYSKYLDSKAAHDFVEWLLSAK (Compound 131) (SEQ ID NO: 131) HSQGTFTSDYSKYLDSKAAHDFVEWLKSA; (Compound 132) (SEQ ID NO: 132) HSQGTFTSDYSKYLDSKAAHDFVKWLLRA; (Compound 133) (SEQ ID NO: 133) HSQGTFTSDYSKYLDSCAAHDFVEWLLRA; (Compound 134) (SEQ ID NO: 134) HSQGTFTSDYSKYLDSCAAHDFVEWLLSA; (Compound 135) (SEQ ID NO: 135) HSQGTFTSDYSKYLDSKAACDFVEWLLRA; (Compound 136) (SEQ ID NO: 136) HSQGTFTSDYSKYLDKSAAHDFVEWLLRA; (Compound 137) (SEQ ID NO: 137) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLSA; (Compound 138) (SEQ ID NO: 138) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLSAK; (Compound 139) (SEQ ID NO: 139) H-Aib-QGTFTSDYSKYLDSKAARDFVAWLLRA; (Compound 140) (SEQ ID NO: 140) H-Aib-QGTFTSDYSKYLDSKAAKDFVAWLLRA; (Compound 141) (SEQ ID NO: 141) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLKA (Compound 142) (SEQ ID NO: 142) H-Aib-QGTFTSDYSKYLDSKAAKDFVAWLLSA (Compound 143) (SEQ ID NO: 143) H-Aib-QGTFTSDYSKYLDSKAAHDFVAWLLKA; (Compound 144) (SEQ ID NO: 144) H-Aib-QGTFTSDYSKYLDKKAAHDFVAWLLRA; (Compound 145) (SEQ ID NO: 145) H-Aib-QGTFTSDYSRYLDSKAAHDFVEWLLSA; (Compound 146) (SEQ ID NO: 146) H-Aib-QGTFTSDYSKYLDSKAAHDFVKWLLSA; (Compound 147) (SEQ ID NO: 147) H-Aib-QGTFTSDYSLYLDSKAAHDFVEWLLSA; (Compound 148) (SEQ ID NO: 148) H-Aib-QGTFTSDYSKYLDSCAAHDFVEWLLSA; (Compound 149) (SEQ ID NO: 149) H-Aib-QGTFTSDYSKYLDSKAACDFVEWLLRA; (Compound 150) (SEQ ID NO: 150) H-Aib-QGTFTSDYSKYLDK( )KAAE( )DFVEWLLRA; (Compound 151) (SEQ ID NO: 151) H-Aib-QGTFTSDYSKYLDSKAAHDFVE( )WLLK( )A (Compound 152) (SEQ ID NO: 152) H-Aib-QGTFTSDYSKYLDSKAAK( )DFVE( )WLLRA; (Compound 153) (SEQ ID NO: 153) H-Aib-QGTFTSDYSKYLDSK( )AAHE( )FVEWLLKA; or (Compound 154) (SEQ ID NO: 154) H-Aib-QGTFTSDYSKYLDSK( )AAKE( )FVEWLLRA. (Compound 155) (SEQ ID NO: 155) HSQGTFTSDYSKYLDRARADDFVAWLKSA; (Compound 156) (SEQ ID NO: 156) HSQGTFTSDYSKYLDRARADDFVAWLKEA; (Compound 157) (SEQ ID NO: 157) HSQGTFTSDYSKYLDRARAEDFVAWLKST; (Compound 158) (SEQ ID NO: 158) HSQGTFTSDYSKYLDRARADDFVEWLKST; (Compound 159) (SEQ ID NO: 159) H-DSer-QGTFTSDYSKYLDRARADDFVAWLKST; (Compound 160) (SEQ ID NO: 160) HSQGTFTSDYSKYLDRARAHDFVAWLKST; (Compound 161) (SEQ ID NO: 161) HSQGTFTSDYSKYLDKARADDFVAWLKST; (Compound 162) (SEQ ID NO: 162) HSQGTFTSDYSKYLDRAKADDFVAWLKST; (Compound 163) (SEQ ID NO: 163) HSQGTFTSDYSKYLDRARAKDFVAWLKST, or (Compound 164) (SEQ ID NO: 164) HSQGTFTSDYSKYLDRARADDFVKWLKST

[0238] In certain embodiments these peptides may carry a lipophilic substituent at the position marked "*" as follows:

TABLE-US-00069 (Compound 165) (SEQ ID NO: 165) HSQGTFTSDYSKYLDS-K*-AAHDFVEWLLRA; (Compound 166) (SEQ ID NO: 166) HSQGTFTSDYSKYLD-K*-KAAHDFVEWLLRA; (Compound 167) (SEQ ID NO: 167) HSQGTFTSDYSKYLDSKAA-K*-DFVEWLLRA; (Compound 168) (SEQ ID NO: 168) HSQGTFTSDYSKYLDSKAAHDFVEWL-K*-RA; (Compound 169) (SEQ ID NO: 169) HSQGTFTSDYSKYLDSKAAHDFVEWLL-K*-A; (Compound 170) (SEQ ID NO: 170) HSQGTFTSDYSRYLDS-K*-AAHDFVEWLLRA; (Compound 171) (SEQ ID NO: 171) HSQGTFTSDYSLYLDS-K*-AAHDFVEWLLRA; (Compound 172) (SEQ ID NO: 172) HSQGTFTSDYSKYLDSKAAHDFVEWLLRA-K*; (Compound 173) (SEQ ID NO: 173) HSQGTFTSDYSKYLDSKAAHDFVEWLLSA-K*; (Compound 174) (SEQ ID NO: 174) HSQGTFTSDYSKYLDSKAAHDFVEWL-K*-SA; (Compound 175) (SEQ ID NO: 175) HSQGTFTSDYSKYLDSKAAHDFV-K*-WLLRA; (Compound 176) (SEQ ID NO: 176) HSQGTFTSDYSKYLDS-C*-AAHDFVEWLLRA; (Compound 177) (SEQ ID NO: 177) HSQGTFTSDYSKYLDS-C*-AAHDFVEWLLSA; (Compound 178) (SEQ ID NO: 178) HSQGTFTSDYSKYLDSKAA-C*-DFVEWLLRA; (Compound 179) (SEQ ID NO: 179) HSQGTFTSDYSKYLD-K*-SAAHDFVEWLLRA; (Compound 180) (SEQ ID NO: 180) H-Aib-QGTFTSDYSKYLDS-K*-AAHDFVEWLLSA; (Compound 181) (SEQ ID NO: 181) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLSA-K*; (Compound 182) (SEQ ID NO: 182) H-Aib-QGTFTSDYSKYLDS-K*-AARDFVAWLLRA; (Compound 183) (SEQ ID NO: 183) H-Aib-QGTFTSDYSKYLDSKAA-K*-DFVAWLLRA; (Compound 184) (SEQ ID NO: 184) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLL-K*-A; (Compound 185) (SEQ ID NO: 185) H-Aib-QGTFTSDYSKYLDS-K*-AAHDFVEWLLKA; (Compound 186) (SEQ ID NO: 186) H-Aib-QGTFTSDYSKYLDS-K*-AAHDFVEWLLRA; (Compound 187) (SEQ ID NO: 187) H-Aib-QGTFTSDYSKYLDSKAA-K*-DFVAWLLSA; (Compound 188) (SEQ ID NO: 188) H-Aib-QGTFTSDYSKYLDSKAAHDFVAWLL-K*-A; (Compound 189) (SEQ ID NO: 189) H-Aib-QGTFTSDYSKYLD-K*-KAAHDFVAWLLRA; (Compound 190) (SEQ ID NO: 190) H-Aib-QGTFTSDYSRYLDS-K*-AAHDFVEWLLSA; (Compound 191) (SEQ ID NO: 191) H-Aib-QGTFTSDYSKYLDSKAAHDFV-K*-WLLSA; (Compound 192) (SEQ ID NO: 192) H-Aib-QGTFTSDYSLYLDS-K*-AAHDFVEWLLSA; (Compound 193) (SEQ ID NO: 193) H-Aib-QGTFTSDYSKYLDS-C*-AAHDFVEWLLSA; (Compound 194) (SEQ ID NO: 194) H-Aib-QGTFTSDYSKYLDSKAA-C*-DFVEWLLRA; (Compound 195) (SEQ ID NO: 195) H-Aib-QGTFTSDYSKYLD-S*-KAAHDFVEWLLSA; (Compound 196) (SEQ ID NO: 196) H-Aib-QGTFTSDYSKYLDK( )K*AAE( )DFVEWLLRA; (Compound 197) (SEQ ID NO: 197) H-Aib-QGTFTSDYSKYLDSK*AAHDFVE( )WLLK( )A; (Compound 198) (SEQ ID NO: 198) H-Aib-QGTFTSDYSKYLDSK*AAK( )DFVE( )WLLRA; (Compound 199) (SEQ ID NO: 199) H-Aib-QGTFTSDYSKYLDSK( )AAHE( )FVEWLLK*A; or (Compound 200) (SEQ ID NO: 200) H-Aib-QGTFTSDYSKYLDSK( )AAK*E( )FVEWLLRA. Residues marked "( )" participate in an intramolecular bond, such as a lactam ring, as described above.

[0239] In particular embodiments, the derivatised peptide X has the formula:

TABLE-US-00070 (Compound 201) (SEQ ID NO: 201) HSQGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AAHDFVEWLLRA; (Compound 202) (SEQ ID NO: 202) HSQGTFTSDYSKYLD-K(Hexadecanoyl-.gamma.-Glu)-KAAHDFVEWLLRA; (Compound 203) (SEQ ID NO: 203) HSQGTFTSDYSKYLDSKAAHDFVEWL-K(Hexadecanoyl-.gamma.-Glu)-RA; (Compound 204) (SEQ ID NO: 204) HSQGTFTSDYSKYLDSKAA-K(Hexadecanoyl-.gamma.-Glu)-DFVEWLLRA; (Compound 205) (SEQ ID NO: 205) HSQGTFTSDYSKYLDSKAAHDFVEWLL-K(Hexadecanoyl-.gamma.-Glu)-A; (Compound 206) (SEQ ID NO: 206) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AAHDFVEWLLRA; (Compound 207) (SEQ ID NO: 207) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AARDFVAWLLRA; (Compound 208) (SEQ ID NO: 208) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 209) (SEQ ID NO: 209) H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLL-K(Hexadecanoyl-.gamma.-Glu)-A; (Compound 210) (SEQ ID NO: 210) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AAHDFVE( )WLLK( )A; (Compound 211) (SEQ ID NO: 211) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AAHDFVEWLLKA; (Compound 212) (SEQ ID NO: 212) HSQGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)-AAHDFVEWLLRA; (Compound 213) (SEQ ID NO: 213) H-Aib-QGTFTSDYSKYLDSKAA-K(Hexadecanoyl-.gamma.-Glu)-DFVAWLLRA; (Compound 214) (SEQ ID NO: 214) H-Aib-QGTFTSDYSKYLDS-K(Dodecanoyl-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 215) (SEQ ID NO: 215) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[3-aminopropanoyl])-AAHDFVEWLLSA; (Compound 216) (SEQ ID NO: 216) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[8-aminooctanoyl])-AAHDFVEWLLSA; (Compound 217) (SEQ ID NO: 217) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.epsilon.-Lys)-AAHDFVEWLLSA: (Compound 218) (SEQ ID NO: 218) HSQGTFTSDYSKYLDS-K(Hexadecanoyl)-AAHDFVEWLLSA; (Compound 219) (SEQ ID NO: 219) HSQGTFTSDYSKYLDS-K(Octadecanoyl-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 220) (SEQ ID NO: 220) HSQGTFTSDYSKYLDS-K([2-Butyloctanoyl]-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 221) (SEQ ID NO: 221) HSQGTFTSDYSKYLDS-K(Hexadecanoyl-[4-Aminobutanoyl])-AAHDFVEWLLSA; (Compound 222) (SEQ ID NO: 222) HSQGTFTSDYSKYLDS-K(Octadecanoyl-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 223) (SEQ ID NO: 223) HSQGTFTSDYSKYLDS-K(Hexadecanoyl-E)-AAHDFVEWLLSA; (Compound 224) (SEQ ID NO: 224) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl)-AAHDFVEWLLSA; (Compound 225) (SEQ ID NO: 225) H-Aib-QGTFTSDYSKYLDS-K(Octadecanoyl-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 226) (SEQ ID NO: 226) H-Aib-QGTFTSDYSKYLDS-K([2-Butyloctanoyl]-.gamma.-Glu)-AAHDFVEWLLSA; (Compound 227) (SEQ ID NO: 227) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[4-Aminobutanoyl])-AAHDFVEWLLSA; (Compound 228) (SEQ ID NO: 228) HSQGTFTSDYSKYLDRARADDFVAWLK(Hexadecanoyl-.gamma.-Glu)-SA; (Compound 229) (SEQ ID NO: 229) HSQGTFTSDYSKYLDRARADDFVAWLK(Hexadecanoyl-.gamma.-Glu)-EA; (Compound 230) (SEQ ID NO: 230) HSQGTFTSDYSKYLDRARAEDFVAWLK(Hexadecanoyl-.gamma.-Glu)-ST; (Compound 231) (SEQ ID NO: 231) HSQGTFTSDYSKYLDRARADDFVEWLK(Hexadecanoyl-.gamma.-Glu)-ST; (Compound 232) (SEQ ID NO: 232) H-DSer-QGTFTSDYSKYLDRARADDFVAWLK(Hexadecanoyl-.gamma.-Glu)-ST; (Compound 233) (SEQ ID NO: 233) HSQGTFTSDYSKYLDRARAHDFVAWLK(Hexadecanoyl-.gamma.-Glu)-ST; (Compound 234) (SEQ ID NO: 234) HSQGTFTSDYSKYLDRARADDFVAWLK(Hexadecanoyl-.gamma.-Glu)-ST; (Compound 235) (SEQ ID NO: 235) HSQGTFTSDYSKYLDK(Hexadecanoyl-.gamma.-Glu)-ARADDFVAWLKST; (Compound 236) (SEQ ID NO: 236) HSQGTFTSDYSKYLDRAK(Hexadecanoyl-.gamma.-Glu)-ADDFVAWLKST; (Compound 237) (SEQ ID NO: 237) HSQGTFTSDYSKYLDRARAK(Hexadecanoyl-.gamma.-Glu)-DFVAWLKST; (Compound 238) (SEQ ID NO: 238) HSQGTFTSDYSKYLDRARADDFVK(Hexadecanoyl-.gamma.-Glu)-WLKST; (Compound 239) (SEQ ID NO: 239) H-Aib-QGTFTSDYSKYLDS-K(Octadecanoyl-.gamma.-Glu)-AAHDFVEWLLSA; or (Compound 240) (SEQ ID NO: 240) H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-E)-AAHDFVEWLLSA. Residues marked "( )" participate in an intramolecular bond, such as a lactam ring.

[0240] Alternatively or additionally, one or more amino acid side chains in the compound of the invention may be conjugated to a polymeric moiety, for example, in order to increase solubility and/or half-life in vivo (e.g. in plasma) and/or bioavailability. Such modification is also known to reduce clearance (e.g. renal clearance) of therapeutic proteins and peptides.

[0241] The polymeric moiety is preferably water soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymeric moieties include polyethylene glycol (PEG), homo- or co-polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998); Bioconjugate Chem. 6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992).

[0242] Other suitable polymeric moieties include poly-amino acids such as poly-lysine, poly-aspartic acid and poly-glutamic acid (see for example Gombotz, et al. (1995), Bioconjugate Chem., vol. 6: 332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57; Tsukada, et al. (1984), J. Natl. Cancer Inst., vol 73, :721-729; and Pratesi, et al. (1985), Br. J. Cancer, vol. 52: 841-848).

[0243] The polymeric moiety may be straight-chain or branched. It may have a molecular weight of 500-40,000 Da, for example 500-5,000 Da, 500-10,000 Da, 1000-5000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

[0244] A compound may comprise two or more such moieties, in which case the total molecular weight of all such moieties will generally fall within the ranges provided above.

[0245] The polymeric moiety may be coupled (by covalent linkage) to an amino, carboxyl or thiol group of an amino acid side chain. Preferred examples are the thiol group of Cys residues and the epsilon amino group of Lys residues, and the carboxyl groups of Asp and Glu residues may also be used.

[0246] For example, the polymeric moiety may be coupled to the side chain of the residue at one or more of positions 16, 17 18, 20, 21, 24 or 29, or to the C-terminus of the peptide. For example, it may be coupled at one or more of positions 16, 17, 21 and 24.

[0247] The skilled reader will be well aware of suitable techniques which can be used to perform the coupling reaction. For example, a PEG moiety carrying a methoxy group can be coupled to a Cys thiol group by a maleimido linkage using regents commercially available from Nektar Therapeutics AL. See also WO 2008/101017, and the references cited above for details of suitable chemistry.

Biological Activity

[0248] Binding of the relevant compounds to GLP-1 or glucagon (Glu) receptors may be used as an indication of agonist activity, but in general it is preferred to use a biological assay which measures intracellular signalling caused by binding of the compound to the relevant receptor. For example, activation of the glucagon receptor by a glucagon agonist will stimulate cellular cyclic AMP (cAMP) formation. Similarly, activation of the GLP-1 receptor by a GLP-1 agonist will stimulate cellular cAMP formation. Thus, production of cAMP in suitable cells expressing one of these two receptors can be used to monitor the relevant receptor activity. Use of a suitable pair of cell types, each expressing one receptor but not the other, can hence be used to determine agonist activity towards both types of receptor.

[0249] The skilled person will be aware of suitable assay formats, and examples are provided below. The GLP-1 receptor and/or the glucagon receptor may have the sequence of the receptors as described in the examples. For example, the assays may make use of the human glucagon receptor (Glucagon-R) having primary accession number GI:4503947 and/or the human glucagon-like peptide 1 receptor (GLP-1R) having primary accession number GI:166795283. (Where sequences of precursor proteins are referred to, it should of course be understood that assays may make use of the mature protein, lacking the signal sequence).

[0250] EC.sub.50 values may be used as a numerical measure of agonist potency at a given receptor. An EC.sub.50 value is a measure of the concentration of a compound required to achieve half of that compound's maximal activity in a particular assay. Thus, for example, a compound having EC.sub.50[GLP-1] lower than the EC.sub.50[GLP-1R] of glucagon in a particular assay may be considered to have higher potency at the GLP-1R than glucagon.

[0251] The compounds described in this specification are typically Glu-GLP-1 (glucagon-GLP-1) dual agonists, i.e. they are capable of stimulating cAMP formation at both the glucagon receptor and the GLP-1 receptor. The stimulation of each receptor can be measured in independent assays and afterwards compared to each other.

[0252] By comparing the EC.sub.50 value for the glucagon receptor (EC.sub.50 [Glucagon-R]) with the EC.sub.50 value for the GLP-1 receptor, (EC.sub.50 [GLP-1R]) for a given compound the relative glucagon selectivity (%) of that compound can be found:

Relative Glucagon-R selectivity[Compound]=(1/EC.sub.50[Glucagon-R]).times.100/(1/EC.sub.50[Gl- ucagon-R]+1/EC.sub.50[GLP-1R])

[0253] The relative GLP-1R selectivity can likewise be found:

Relative GLP-1R selectivity[Compound]=(1/EC.sub.50[GLP-1R]).times.100/(1/EC.sub.50[Glucag- on-R]+1/EC.sub.50[GLP-1R])

[0254] A compound's relative selectivity allows its effect on the GLP-1 or glucagon receptor to be compared directly to its effect on the other receptor. For example, the higher a compound's relative GLP-1 selectivity is, the more effective that compound is on the GLP-1 receptor as compared to the glucagon receptor.

[0255] Using the assays described below, we have found the relative GLP-1 selectivity for human glucagon to be approximately 5%.

[0256] Compounds suitable for use in the methods of the invention typically have a higher relative GLP-1R selectivity than human glucagon. Thus, for a particular level of glucagon-R agonist activity, the compound will display a higher level of GLP-1R agonist activity (i.e. greater potency at the GLP-1 receptor) than glucagon. It will be understood that the absolute potency of a particular compound at the glucagon and GLP-1 receptors may be higher, lower or approximately equal to that of native human glucagon, as long as the appropriate relative GLP-1R selectivity is achieved.

[0257] Nevertheless, the compounds may have a lower EC.sub.50 [GLP-1R] than human glucagon. The compounds may have a lower EC.sub.50 [GLP-1-R] than glucagon while maintaining an EC.sub.50 [Glucagon-R] that is less than 10-fold higher than that of human glucagon, less than 5-fold higher than that of human glucagon, or less than 2-fold higher than that of human glucagon.

[0258] The compounds may have an EC.sub.50 [Glucagon-R] that is less than two-fold that of human glucagon. The compounds may have an EC.sub.50 [Glucagon-R] that is less than two-fold that of human glucagon and have an EC.sub.50 [GLP-1R] that is less than half that of human glucagon, less than a fifth of that of human glucagon, or less than a tenth of that of human glucagon.

[0259] The relative GLP-1 selectivity of the compounds may be between 10% and 95%. For example, the compounds may have a relative selectivity of 10-20%, 10-30%, 20-50%, 30-70%, or 50-80%; or of 30-50%, 40-60%, 50-70% or 75-95%.

Therapeutic Uses

[0260] The methods of the invention are applicable for conditions in which it is desirable to improve cardiac function directly, e.g. where there is a dysfunction of the cardiac muscle (myocardium) itself. Such conditions include myocardial infarction, heart failure and cardiogenic shock. Positive inotropic agents increase the strength of myocardial contraction, and are used to improve hemodynamic parameters and thereby relieve symptoms and protect end-organs in patients with myocardial infarction, cardiogenic shock, or heart failure. Known inotropic agents such as dobutamine, norepinephrine and glucagon exert their effects (increase in cardiac work) at the expense of increased cardiac energy demand and can therefore have a severe depleting effect on the heart's energy reserves (as measured e.g. by total phosphocreatine (PCr), total ATP, or by PCr/ATP, ATP/ADP or ATP/AMP ratios). Since the failing or diseased heart is often energy-starved, the use of inotropic agents may therefore result in energy depletion and consequently in an increased incidence of arrhythmias as well as in increased short- and long-term mortality (Jessup M et al., Circulation 2009; 119:1977-2016). Because of this, current guidelines for treatment of heart failure state that positive inotropic agents should only be considered for palliation of symptoms in patients with refractory end-stage heart failure" (Dickstein K et al., Eur Heart J 2008; 29:2388-2442), and that such agents should be "withdrawn as soon as adequate organ perfusion is restored and/or congestion reduced" (Jessup et al., op cit.). Typically, then, inotropic agents are adminstered only in order to stabilise a patient's condition, but withdrawn after a few hours or a few days.

[0261] Without wishing to be bound by any particular theory, it is believed that the compounds described above for use in the methods of the invention act as glucagon-GLP-1 dual agonists (although they may exert their beneficial cardiac effects by a different mechanism, e.g. via a distinct receptor). They have surprisingly been found to increase cardiac inotropy while simultaneously improving myocardial metabolism, in particular preserving the energetic state of the heart, or at least depleting the reserves of high energy phosphates to a lesser extent than the other inotropic agents discussed above. They are therefore particularly useful for treating an individual suffering from myocardial infarction, heart failure, cardiogenic shock or any other condition where increased cardiac inotropy is desired without compromising the energetic state of the heart, i.e. any abnormality of cardiac function which results in the inability of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues and/or allows it to do so only from an abnormally elevated ventricular diastolic volume. This includes, but is not restricted to; congestive heart failure, systolic dysfunction, diastolic dysfunction, myocardial infarction, ischemic heart disease, diabetic cardiomyopathy, or combinations thereof.

[0262] The myocardial energy status may be monitored by determining total phosphocreatine (PCr), total ATP, or PCr/ATP, ATP/ADP or ATP/AMP ratios. Such determinations may be made by biopsy (e.g. as described in Ally A and Park G. Rapid determination of creatine, phosphocreatine, purine bases and nucleotides (ATP, ADP, AMP, GTP, GDP) in heart biopsies by gradient ion-pair reversed-phase liquid chromatography. J Chromatogr 1992; 575:19-27) or by magnetic resonance spectroscopy (Neubauer S et al., Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997; 96:2190-2196; Yabe T et al., Quantitative measurements of cardiac phosphorus metabolites in coronary artery disease by .sup.31P magnetic resonance spectroscopy. Circulation 1995; 92:15-23).

[0263] By improving myocardial metabolism simultaneously with having positive inotropic effects, the compounds for use in accordance with this invention may be associated with fewer arrhythmias and/or lower mortality than current positive inotropic agents. Consequently, the methods of the invention may be used for patients with less severe disease and/or for longer periods of time in those with severe heart failure, than is currently recommended.

[0264] For example, the subject may be treated with a suitable compound for a period greater than 12 hours, greater than 24 hours, greater than 36 hours or greater than 48 hours. For example, the subject may be treated for a period greater than 3 days, e.g. greater than 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. The patient may be treated for a period greater than 2 weeks, greater than 3 weeks or greater than 4 weeks. The patient may be treated for a period greater than 1 month, 2 months, 3 months, 4 months, r 5 months. i.e. chronic/lifelong treatment.

[0265] The patient may be treated for a period between 1 week and 6 weeks, e.g. between 2 weeks and 6 weeks, between 3 weeks and 6 weeks, between 4 weeks and 6 weeks or between 5 weeks and 6 weeks.

[0266] The patient may be treated for a period between 1 week and 5 weeks, e.g. between 2 weeks and 5 weeks, between 3 weeks and 5 weeks, between 4 weeks and 5 weeks.

[0267] The patient may be treated for a period between 1 week and 4 weeks, e.g. between 2 weeks and 4 weeks, between 3 weeks and 4 weeks.

[0268] The patient may be treated for a period between 1 week and 3 weeks, e.g. between 2 weeks and 3 weeks.

[0269] For example, the patient may be treated for a period between 1 week and 6 months, e.g. between 1 week and 5 months, between 1 week and 4 months, between 1 week and 3 months, between 1 week and 2 months, or between 1 week and 1 month.

[0270] The patient may be treated for a period between 2 weeks and 6 months, e.g. between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, or between 2 weeks and 1 month.

[0271] The patient may be treated for a period between 3 weeks and 6 months, e.g. between 3 weeks and 5 months, between 3 weeks and 4 months, between 3 weeks and 3 months, between 3 weeks and 2 months, or between 3 weeks and 1 month.

[0272] The patient may be treated for a period between 4 weeks and 6 months, e.g. between 4 weeks and 5 months, between 4 weeks and 4 months, between 4 weeks and 3 months, between 4 weeks and 2 months, or between 4 weeks and 1 month.

[0273] The patient may be treated for a period between 1 month and 6 months, e.g. between 2 months and 6 months, between 3 months and 6 months, between 4 months and 6 months, between 5 months and 6 months.

[0274] The patient may be treated for a period between 1 month and 5 months, e.g. between 2 months and 5 months, between 3 months and 5 months, between 4 months and 5 months.

[0275] The patient may be treated for a period between 1 month and 3 months, e.g. between 2 months and 3 months.

[0276] The patient may be treated for a period between 1 month and 2 months.

[0277] In some cases in accordance with the present invention treatment may comprise a dosage regime of continuous infusion, twice daily or once daily.

[0278] Other dosage regimes are contemplated, including a dosage regime that may be once daily, twice daily, once weekly, once bi-weekly or once monthly.

Pharmaceutical Compositions

[0279] The compounds described for use in this invention, or salts thereof, may be formulated as pharmaceutical compositions prepared for storage or administration, which typically comprise a therapeutically effective amount of a compound or salt thereof in a pharmaceutically acceptable carrier.

[0280] The precise amount to be administered will depend on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts. The dosage levels and dosing regimen most appropriate for human use may be established on the basis of the results obtained by the present invention, and may be confirmed in properly designed clinical trials.

[0281] An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person.

[0282] The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used. pH buffering agents may be phosphate, citrate, acetate, tris/hydroxymethyl)aminomethane (TRIS), N-Tris(hydroxymethyl)methyl-3-aminopropanesulphonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, which is a preferred buffer, arginine, lysine, or acetate or mixtures thereof. The term further encompases any agents listed in the US Pharmacopeia for use in animals, including humans.

[0283] The term "pharmaceutically acceptable salt" refers to the salts of the dual agonist compounds. Pharmaceutically acceptable salts typically include acid addition salts and basic salts. Examples of pharmaceutically acceptable acid addition salts include hydrochloride salts, citrate salts and acetate salts. Examples of pharmaceutically acceptable basic salts include salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions .sup.+N(R.sup.3).sub.3(R.sup.4), where R.sup.3 and R.sup.4 independently designates optionally substituted C.sub.1-6-alkyl, optionally substituted C.sub.2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl. Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and more recent editions, and in the Encyclopaedia of Pharmaceutical Technology.

[0284] "Treatment" is an approach for obtaining beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. "Treatment" is an intervention performed with the intention of preventing the development of, or altering the pathology of, a disorder. Accordingly, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented

[0285] The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. It may be provided in single dose injectable form, for example in the form of a pen. Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0286] Intravenous, subcutaneous or transdermal modes of administration may be particularly suitable for the compounds described herein.

Combination Therapy

[0287] The compounds described above may be administered as part of a combination therapy with an agent for treatment of heart failure, diabetes, obesity, myocardial infarction, hypertension, or hypolipidemia.

[0288] In such cases, the two active agents may be given together or separately, and as part of the same pharmaceutical formulation or as separate formulations.

[0289] Thus the compound (or salt thereof) can be used in combination with an anti-diabetic agent including but not limited to metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, or insulin. In a preferred embodiment the compound or salt thereof is used in combination with insulin, DPP-IV inhibitor, sulfonylurea or metformin, particularly sulfonylurea or metformin, for achieving adequate glycemic control. In an even more preferred embodiment the compound or salt thereof is used in combination with insulin or an insulin analogue for achieving adequate glycemic control. Examples of insulin analogues include but are not limited to Lantus.TM., Novorapid.TM., Humalog.TM., Novomix.TM., and Actraphane HM.TM..

[0290] The compound or salt thereof can further be used in combination with an anti-obesity agent including but not limited to a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist.

[0291] The analogue compound or salt thereof can be used in combination with an anti-hypertension agent including but not limited to an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), diuretics, beta-blocker, or calcium channel blocker.

[0292] The analogue compound or salt thereof can in particular be used in combination with an agent for treatment of myocardial infarction, heart failure or cardiogenic shock including but not limited to diuretics, angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), aldosterone antagonists, digitalis, acute ionotropes and inotropic dilators.

[0293] The analogue compound or salt thereof can in particular be used in combination with classes of hypolipidemic drugs such as cholesterol lovering agents including but not limited to statins (HMG-CoA reductase inhibitors), fibrates and niacin.

Recombinant Expression

[0294] The compounds for use in the invention may be expressed by recombinant techniques, particularly when they consist entirely of naturally occurring amino acids. For recombinant expression, nucleic acids encoding the relevant compounds will normally be inserted in suitable vectors to form cloning or expression vectors carrying the coding sequences. The vectors can, depending on purpose and type of application, be in the form of plasmids, phages, cosmids, mini-chromosomes, or virus, but also naked DNA which is only expressed transiently in certain cells is an important vector. Cloning and expression vectors (plasmid vectors) may be capable of autonomous replication, thereby enabling high copy-numbers for the purposes of high-level expression or high-level replication for subsequent cloning.

[0295] In general outline, an expression vector comprises the following features in the 5'.fwdarw.3' direction and in operable linkage: a promoter for driving expression of the relevant coding nucleic acid, optionally a nucleic acid sequence encoding a leader peptide enabling secretion (to the extracellular phase or, where applicable, into the periplasma), the nucleic acid fragment encoding the compound, and optionally a nucleic acid sequence encoding a terminator. They may comprise additional features such as selectable markers and origins of replication. When operating with expression vectors in producer strains or cell lines it may be preferred that the vector is capable of integrating into the host cell genome. The skilled person is very familiar with suitable vectors and is able to design one according to their specific requirements.

[0296] The vectors of the invention are used to transform host cells to produce the compound. Such transformed cells can be cultured cells or cell lines used for propagation of the nucleic acid fragments and vectors of the invention, or used for recombinant production of the peptides of the invention.

[0297] Preferred host cells are micro-organisms such as bacteria (such as the species Escherichia (e.g. E. coli), Bacillus (e.g. Bacillus subtilis), Salmonella, or Mycobacterium (preferably non-pathogenic, e.g. M. bovis BCG), yeasts (such as Saccharomyces cerevisiae), and protozoans. Alternatively, the host cell may be derived from a multicellular organism, i.e. it may be fungal cell, an insect cell, a plant cell, or a mammalian cell. For the purposes of cloning and/or optimised expression it is preferred that the host cell is capable of replicating the nucleic acid fragment or vector as applicable. Cells expressing the nucleic fragment are useful embodiments of the invention; they can be used for small-scale or large-scale preparation of the compounds.

[0298] When producing the compound by means of transformed cells, it is convenient, although far from essential, that the expression product is secreted into the culture medium.

[0299] It will be understood that such nucleic acids, expression vectors and host cells may be used for treatment of any of the conditions described herein which may be treated with the compounds themselves. For example, nucleic acids encoding the compounds, particularly expression vectors containing such nucleic acids, may be suitable for direct administration to a subject so that the nucleic acid is taken up and the compound produced by the subject's own cells. The compound is preferably secreted by the cells containing the nucleic acid. Similarly, host cells capable of producing and secreting the compound may be administered to a subject so that the compound is produced in situ. The host cells may be treated (e.g. encapsulated) to inhibit or reduce their immunogenicity to the recipient subject. References to a therapeutic composition comprising a compound, administration of a compound, or any therapeutic use of such a compound, should therefore be construed to encompass the equivalent use of a nucleic acid, expression vector or host cell as described herein except where the context demands otherwise.

EXAMPLES

Example 1

Assessment of Inotropic Effect in Working Heart Model

[0300] The effect of the inotropic compound glucagon and a glucagon-GLP-1 dual-agonist (Compound 12 having the sequence HSQGTFTSDYSKYLDRARADDFVAWLKST (SEQ ID NO: 12)) on cardiac function, metabolism, and energy state was evaluated in isolated working hearts (Lopaschuk, G D and Barr, R L. Measurements of fatty acid and carbohydrate metabolism in the isolated working rat heart. Molecular and Cellular Biochemistry. 1997; 172: 137-147) from control and insulin-resistant JCR:LA-cp rats. Isolated working hearts were subjected to aerobic perfusion with Krebs-Henseleit solution (11 mM glucose, 2000 .mu.U/ml insulin, 1.25 mM free Ca.sup.2+, 0.8 mM palmitate, and 3% BSA) and during perfusion increasing concentrations (10, 50, and 100 mM) of glucagon or Compound 12 was added to the perfusion buffer. Following perfusions, high energy phosphate nucleotide concentrations were measured by high performance liquid chromatography (HPLC) (Ally, A and Park, G. Rapid determination of creatine, phosphocreatine, purine bases and nucleotides (ATP, ADP, AMP, GTP, GDP) in heart biopsies by gradient ion-pair reversed-phase liquid chromatography. Journal of Chromatography. 1992; 575: 19-27).

[0301] Glucagon and Compound 12 had similar inotropic effects on cardiac function in both normal (data not shown) and insulin-resistant JCR-LA rats (FIG. 1). Despite similar effects on cardiac function and thereby cardiac energy demand, glucagon and Compound 12 had statistically significant different effects on the energetic state of insulin resistant hearts (FIG. 2). Specifically, treatment with glucagon caused statistically significant increases in AMP and ADP levels and thereby decreased ATP/AMP and ATP/ADP ratios. However, following treatment with Compound 12 the energetic state of the hearts was not significantly different from vehicle perfused hearts. No effect was observed with the GLP-1 agonist exendin-4[1-39]-K.sub.6 (H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAS-K.sub.6--NH.sub.2) (Compound 241) (SEQ ID NO: 241) (data not shown).

Example 2

Determination of Efficacy at GLP-1 and Glucagon Receptors

[0302] HEK293 cells expressing the human glucagon receptor or human GLP-1R (see above for details) were seeded at 40,000 cells per well in 96-well microtiter plates coated with 0.01% poly-L-lysine and grown for 1 day in culture in 100 .mu.l growth medium. On the day of analysis, growth medium was removed and the cells washed once with 200 .mu.l Tyrode buffer. Cells were incubated in 100 Tyrode buffer containing increasing concentrations of test peptides, 100 .mu.M IBMX, and 6 mM glucose for 15 min at 37.degree. C. The reaction was stopped by addition of 25 .mu.l 0.5 M HCl and incubated on ice for 60 min. The cAMP content was estimated using the FlashPlate.RTM. cAMP kit from Perkin-Elmer. EC.sub.50 values were estimated by computer aided curve fitting.

[0303] Table 1 shows results for sample compounds as EC.sub.50 values.

TABLE-US-00071 Compound EC.sub.50 EC.sub.50 No./SEQ (nM) (nM) ID NO: Test compound GLP-1R GuR 1 H-HSQGTFTSDYSKYLDSRRAQDFVWLMNT-OH 2.0 0.1 (Human glucagon) 12 H-HSQGTFTSDYSKYLDRARADDFVAWLKST-NH2 0.23 0.50 242 H-HSQGTFTSDYSAYLDSRRAQDFVWLMNT-NH2 1.4 0.4 243 H-HSQGTFTSDYSKYLDSERAQDFVWLMNT-NH2 0.6 0.06 244 H-HSQGTFTSDYSKYLDSRHAQDFVWLMNT-NH2 0.5 0.05 245 H-HSQGTFTSDYSKYLDSRSAQDFVWLMNT-NH2 0.1 0.05 246 H-HSQGTFTSDYSKYLDSRAAQDFVWLMNT-NH2 0.3 0.05 247 H-HSQGTFTSDYSKYLDSRYAQDFVWLMNT-NH2 0.3 0.1 248 H-HSQGTFTSDYSKYLDSRRAQDFVWLESA-NH2 0.5 0.1 249 H-HSQGTFTSDYSKYLDSRRAQDFVWLKSA-NH2 0.1 0.1 250 H-HSQGTFTSDYSKYLDSRRAQDFVWLKRA-NH2 0.3 0.1 251 H-HSQGTFTSDYSKYLDSRRAQDFVWLERA-NH2 0.2 0.1 252 H-HSQGTFTSDYSRYLDSRRAKDFVWLLNT-NH2 0.5 0.3 253 H-HSQGTFTSDYSRYLDSRRAQDFVWLLNT-NH2 0.2 0.1 254 H-HSQGTFTSDYSRYLDSRRAQDFVWLLNK-NH2 0.2 0.2 255 H-HSQGTFTSDYSKYLDSALAQDFVWLLNT-NH2 0.24 0.1 256 H-HSQGTFTSDYSKYLDKRRAEDFVWLMNT-NH2 0.2 0.07 257 H-HSQGTFTSDYSKYLDK( )RRAE( )DFVWLMNT-NH2 0.1 0.09 258 H-HSQGTFTSDYSRYLDERRAQDFVWLMNT-NH2 0.07 0.06 259 H-HSQGTFTSDYSK( )YLDE( )RRAQDFVWLMNT-NH2 0.04 0.03 120 H-HSQGTFTSDYSKYLDSRRAQDFIEWLMNT-NH2 0.2 0.2 260 H-HSQGTFTSDYSKYLDSKAAQDFVWLMNT-NH2 0.02 0.07 48 H-HSQGTFTSDYSKYLDSKAAHDFVEWLLRA-NH2 0.06 0.06 44 H-H-DSer-QGTFTSDYSKYLDSKAAHDFVEWLLRA-NH2 0.09 0.11 45 H-H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA-NH2 0.08 0.06 261 H-HSQGTFTSDYSKYLDSKAAHDFVE( )WLLK( )A-NH2 0.03 0.07 202 H-HSQGTFTSDYSKYLD-K(Hexadecanoyl-.gamma.-Glu)- 0.20 0.13 KAAHDFVEWLLRA-NH2 262 H-HSQGTFTSDYSKYLD-S-K(Hexadecanoyl-.gamma.-Glu)- 0.11 0.12 AAHDFVEWLLRA-NH2 204 H-HSQGTFTSDYSKYLDSKAA-K(Hexadecanoyl-.gamma.-Glu)- 0.10 0.04 DFVEWLLRA-NH2 203 H-HSQGTFTSDYSKYLDSKAAHDFVEWL-K(Hexadecanoyl-.gamma.- 0.57 0.22 Glu)-RA-NH2 205 H-HSQGTFTSDYSKYLDSKAAHDFVEWLL-K(Hexadecanoyl-.gamma.- 0.09 0.10 Glu)-A-NH2 208 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)- 0.11 0.16 AAHDFVEWLLSA-NH2 263 H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-.gamma.-Glu)- 0.10 0.16 RAKDFIEWLLSA-NH2 207 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)- 0.12 0.17 AARDFVAWLLRA-NH2 213 H-H-Aib-QGTFTSDYSKYLDSKAA-K(Hexadecanoyl-.gamma.-Glu)- 0.15 0.63 DFVAWLLRA-NH2 206 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)- 0.09 0.16 AAHDFVEWLLRA-NH2 209 H-H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLL-K(Hexadecanoyl- 0.27 0.27 .gamma.-Glu)-A-NH2 210 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.gamma.-Glu)- 0.08 0.26 AAHDFVE( )WLLK( )A-NH2 214 H-H-Aib-QGTFTSDYSKYLDS-K(Dodecanoyl-.gamma.-Glu)- 0.14 0.78 AAHDFVEWLLSA-NH2 215 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[3- 0.23 1.87 Aminopropanoyl])-AAHDFVEWLLSA-NH2 216 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[8- 0.24 0.46 Aminooctanoyl])-AAHDFVEWLLSA-NH2 217 H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-.epsilon.-Lys)- 0.09 0.39 AAHDFVEWLLSA-NH2 Brackets ( ) indicate intramolecular lactam rings.

Example 3

Assessment of Inotropic Effect In Vivo in Aneasthetized Rats

[0304] The effect of the inotropic compound 1 and a glucagon-GLP-1 dual-agonist (Compound 12 on cardiac function, and heart rate was examined in anesthetized male Sprague-Dawley rats weighing approximately 300-400 g (Taconic).

[0305] The rats were exposed to 5% isoflurane in 1:2 N.sub.2O:O.sub.2 until anesthesia were established. Body temperature was kept constant (37.5.+-.0.5.degree. C.) and the animals were artificially ventilated through an endotracheal cannula and anesthesia was maintained.

[0306] A catheter was inserted into the left femoral vein for drug administration and a pressure-volume catheter was inserted into the left ventricle via the right carotid artery. After instrumentation, isoflurane was delivered in pure O.sub.2 during the experiment. After 20 min of stabilization, baseline data was recorded for 15 min while infusing vehicle (at 7 .mu.L/min). Subsequently, compounds were infused After the infusion of the 2.5 nmol/kg/min dose (or a lower dose if heart rate or stroke work was increased more than 40%), vehicle was infused for 15 minutes after which animals were euthanized.

[0307] The impact of compound 1 and various dual glucagon-GLP-1 agonists (compounds 7, 9, 12, 35, 37, 206) on cardiac hemodynamic parameters was examined in the anaesthetized rats. Cardiac stroke work is descriptive of the work that the ventricle needs to perform in order to eject a volume of blood into the aorta, and thereby a good representative of the inotropic state of the heart. The measured strokework as a function of infusion dose for each compound is shown in the FIG. 4a-d. The horizontal line marks 40% increase in stroke work, which was defined as the maximal increase that should be obtained during the experiment. Compound 1 increase the strokework to approximately 40% in respectively 0.1 and 0.2 nmol/kg/min infusion rates (FIG. 4b and 4c) after which infusion of this compound was stopped. Except from compound 12 and compound 7, all the dual glucagon-GLP-1 agonists increased the strokework to 40% at a given infusion rate. The acylated, and thereby more stable, compound 206 showed a prolonged increase in strokework that outlasted the compound infusion and remained high throughout the final vehicle infusion.

[0308] In the same experiments, heart rate was calculated from the hemomynamic parameters and results are given in FIG. 5 showing the changes in heart rate for each infusion rate. Each bar represents different compound. At 0.1 nmol/kg/min and higher doses, compound 1 showed a significant increase in heart rate compared to control (FIGS. 5b and c). None of the other compounds showed significant dose dependent changes in heart rate, although there was a tendency for both compounds 35 and 37 to increase heart rate at 0.2 and 0.5 nmol/kg/min (FIGS. 5c and d).

[0309] In relation to the above results, while glucacon is known to increase cardiac contractility, the concomitant increase in heart rate results in increase in myocardial oxygen demand, which can precipitate angina in patients with coronary artery disease, and thereby pose a significant risk to the heart failure patient. The present experiments show that dual glucagon-GLP-1 agonists can improve cardiac inotropic state to the same extent as glucagon. but the increase in inotropy seems not to be coupled to increase in heart rate as observed with infusions of glucagon. Taken together, the results presented above indicate that dual glucagon-GLP-1 agonists act by improving the cardiac contractility without causing the concomitant increase in heart rate observed with glucagon.

Sequence CWU 1

1

797129PRTHomo sapiens 1His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 28PRTHomo sapiens 2Lys Arg Asn Arg Asn Asn Ile Ala 1 5 337PRTHomo sapiens 3His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn 20 25 30 Arg Asn Asn Ile Ala 35 429PRTArtificial sequenceSynthetic sequence Formula II in PCT/DK2011/050018 4His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Glu Ala 20 25 529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 5His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Ala 20 25 629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 6His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Glu Ala 20 25 729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 7His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Glu Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 8His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Glu Trp Leu Lys Ser Thr 20 25 929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 9His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Glu Arg Ala 20 25 1029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 10His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 1129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 11His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala His Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 1229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 12His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 1329PRTArtificial sequenceSynthetic sequence Formula III in PCT/DK2011/050018 13His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Glu Ser Ala 20 25 1429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 14His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Ile Glu Trp Leu Glu Ser Ala 20 25 1529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 15His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Glu Ser Ala 20 25 1629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 16His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Gln Trp Leu Glu Ser Ala 20 25 1729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 17His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Glu Ser Thr 20 25 1829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 18His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Met Asn Thr 20 25 1929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 19His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Glu Ser Ala 20 25 2029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 20His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Glu Asp Phe Ile Lys Trp Leu Glu Ser Ala 20 25 2129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 21His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Glu Arg Ala 20 25 2229PRTArtificial sequenceSynthetic sequence Formula IV in PCT/DK2011/050018 22His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 2329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 23His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 2429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 24His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 2529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 25His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Gln Trp Leu Leu Ser Ala 20 25 2629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 26His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 2729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 27His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Asp 1 5 10 15 Arg Arg Ala Arg Asp Phe Ile Asp Trp Leu Leu Ser Ala 20 25 2829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 28His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Ile Lys Trp Leu Leu Ser Ala 20 25 2929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 29His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Arg Trp Leu Leu Ser Ala 20 25 3029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 30His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Arg Ala 20 25 3129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 31His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 3229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 32His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 3329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 33His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Asp Trp Leu Leu Ser Ala 20 25 3429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 34His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Ala Ala 20 25 3529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/05001850018 35His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 3629PRTArtificial sequenceSynthetic sequence Formula V in P CT/DK2011/050018 36His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 3729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 37His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Arg Asp Phe Val Arg Trp Leu Lys Leu Ala 20 25 3829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 38His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 3929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 39His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Arg Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 40His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Gln Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 41His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Gln Trp Leu Leu Arg Ala 20 25 4229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 42His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 4329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 43His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Lys Trp Leu Leu Arg Ala 20 25 4429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 44His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 45His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 46His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 47His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 48His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 4929PRTArtificial sequenceSynthetic sequence Formula VI in PCT/DK2011/050018 49His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 5029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 50His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 5129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 51His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Leu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr 20 25 5229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 52His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Xaa Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr 20 25 5329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 53His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Xaa Phe Val Gln Trp Leu Xaa Asn Thr 20 25 5429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 54His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Xaa Trp Leu Xaa Asn Thr 20 25 5529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 55His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Xaa Phe Val Xaa Trp Leu Xaa Asn Thr 20 25 5629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 56His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Xaa Phe Val Gln Trp Leu Xaa Asn Thr 20 25 5729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 57His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Xaa Trp Leu Xaa

Asn Thr 20 25 5829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 58His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 5929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 59His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr 20 25 6030PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 60His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Glu Trp Leu Met Asn Thr Xaa 20 25 30 6129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 61His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 6229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 62His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 6329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 63His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 6429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 64His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Cys Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr 20 25 6529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 65His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Cys Phe Val Gln Trp Leu Xaa Asn Thr 20 25 6629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 66His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Xaa Asn Thr 20 25 6739PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 67His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 6837PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 68His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Lys Arg Asn 20 25 30 Arg Asn Asn Ile Ala 35 6933PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 69His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Xaa Asn Thr Lys Arg Asn 20 25 30 Arg 7029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 70His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 7139PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 71His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 7229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 72His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 7329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 73His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 7439PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 74His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 7529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 75His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Xaa Thr 20 25 7628PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 76His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 1 5 10 15 Arg Arg Ala Asp Phe Val Gln Trp Leu Met Xaa Thr 20 25 7729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 77His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Xaa Thr 20 25 7829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 78His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Xaa Thr 20 25 7929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 79His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Glu Trp Leu Met Lys Xaa 20 25 8029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 80His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 8129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 81His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Asn Thr 20 25 8229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 82His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 8329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 83His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 8429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 84His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 8531PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 85His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 8629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 86His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Xaa Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 8730PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 87His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 20 25 30 8829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 88His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 8929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 89His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Xaa Xaa Ala Lys Xaa Phe Xaa Xaa Trp Leu Met Asn Thr 20 25 9029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 90Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 9129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 91Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 1 5 10 15 Arg Arg Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 9229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 92Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 1 5 10 15 Arg Arg Ala Lys Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 9329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 93Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Lys Xaa Phe Xaa Glu Trp Leu Xaa Xaa Xaa 20 25 9429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 94Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Xaa Phe Xaa Glu Trp Leu Xaa Lys Xaa 20 25 9540PRTArtificial sequenceSynthetic sequence X-Z1 in PCT/DK2011/050018 95Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Xaa Ala Lys Asp Phe Val Xaa Trp Leu Met Asn Xaa Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 9640PRTArtificial sequenceSynthetic sequence X-Z1 in PCT/DK2011/050018 96Xaa Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Xaa Ala Lys Glu Phe Ile Xaa Trp Leu Met Asn Xaa Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 9729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 97His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Xaa Xaa Phe Val Xaa Trp Leu Xaa Asp Thr 20 25 9838PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 98His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Gly Gly Pro Ser 20 25 30 Ser Gly Pro Pro Pro Ser 35 9929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 99His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Xaa Xaa 20 25 10029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 100His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Xaa Xaa 20 25 10129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 101His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Xaa Xaa 20 25 10229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 102His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Glu Trp Leu Met Lys Xaa 20 25 10329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 103His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ala Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 10429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 104His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 10529PRTArtificial sequenceSynthetic sequence Formula I in PCT/DK2011/050018 105Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Xaa Ser Xaa Tyr Leu Xaa Xaa 1 5 10 15 Xaa Xaa Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 10629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 106His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Glu Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 10729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 107His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 10829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 108His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg His Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 10929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 109His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Ser Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 11029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 110His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 11129PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 111His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Tyr Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 11229PRTArtificial sequenceSynthetic sequence Peptide 'X' in

PCT/DK2011/050018 112His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Leu Asn Thr 20 25 11329PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 113His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr 20 25 11429PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 114His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Lys 20 25 11529PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 115His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Ala Leu Ala Gln Asp Phe Val Gln Trp Leu Leu Asn Thr 20 25 11629PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 116His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 11729PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 117His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 11829PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 118His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 11929PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 119His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 12029PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 120His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Ile Glu Trp Leu Met Asn Thr 20 25 12130PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 121His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Arg 20 25 30 12229PRTArtificial sequenceSynthetic sequence Peptide 'X' in PCT/DK2011/050018 122His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Leu Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 12329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 123His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 12429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 124His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 12529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 125His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Lys Arg Ala 20 25 12629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 126His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 12729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 127His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 12829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 128His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 12930PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 129His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala Lys 20 25 30 13030PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 130His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala Lys 20 25 30 13129PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 131His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Lys Ser Ala 20 25 13229PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 132His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Lys Trp Leu Leu Arg Ala 20 25 13329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 133His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Cys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 13429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 134His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Cys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 13529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 135His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Cys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 13629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 136His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Ser Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 13729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 137His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 13830PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 138His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala Lys 20 25 30 13929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 139His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Arg Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 14029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 140His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 14129PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 141His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 14229PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 142His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Ala Trp Leu Leu Ser Ala 20 25 14329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 143His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Ala Trp Leu Leu Lys Ala 20 25 14429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 144His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala His Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 14529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 145His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 14629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 146His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Lys Trp Leu Leu Ser Ala 20 25 14729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 147His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 14829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 148His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Cys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 14929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 149His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Cys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 15029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 150His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Glu Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 15129PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 151His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 15229PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 152His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 15329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 153His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Glu Phe Val Glu Trp Leu Leu Lys Ala 20 25 15429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 154His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Arg Ala 20 25 15529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 155His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Ala 20 25 15629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 156His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Glu Ala 20 25 15729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 157His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Glu Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 15829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 158His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Glu Trp Leu Lys Ser Thr 20 25 15929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 159His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 16029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 160His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala His Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 16129PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 161His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 16229PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 162His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Lys Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 16329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 163His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Lys Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 16429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 164His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Lys Trp Leu Lys Ser Thr 20 25 16529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 165His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 16629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 166His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 16729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 167His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 16829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 168His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Lys Arg Ala 20 25 16929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 169His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 17029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 170His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5

10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 17129PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 171His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 17230PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 172His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala Lys 20 25 30 17330PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 173His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala Lys 20 25 30 17429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 174His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Lys Ser Ala 20 25 17529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 175His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Lys Trp Leu Leu Arg Ala 20 25 17629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 176His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Cys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 17729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 177His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Cys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 17829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 178His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Cys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 17929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 179His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Ser Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 18029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 180His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 18130PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 181His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala Lys 20 25 30 18229PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 182His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Arg Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 18329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 183His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 18429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 184His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 18529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 185His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 18629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 186His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 18729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 187His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Ala Trp Leu Leu Ser Ala 20 25 18829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 188His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Ala Trp Leu Leu Lys Ala 20 25 18929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 189His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala His Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 19029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 190His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 19129PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 191His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Lys Trp Leu Leu Ser Ala 20 25 19229PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 192His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Leu Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 19329PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 193His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Cys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 19429PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 194His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Cys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 19529PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 195His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 19629PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 196His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Glu Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 19729PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 197His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 19829PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 198His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 19929PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 199His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Glu Phe Val Glu Trp Leu Leu Lys Ala 20 25 20029PRTArtificial sequenceSynthetic sequence 'X' of PCT/DK2011/050018 200His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Arg Ala 20 25 20129PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 201His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 20229PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 202His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 20329PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 203His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Lys Arg Ala 20 25 20429PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 204His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 20529PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 205His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 20629PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 206His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 20729PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 207His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Arg Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 20829PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 208His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 20929PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 209His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 21029PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 210His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 21129PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 211His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 21229PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 212His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 21329PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 213His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Lys Asp Phe Val Ala Trp Leu Leu Arg Ala 20 25 21429PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 214His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 21529PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 215His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 21629PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 216His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 21729PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 217His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 21829PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 218His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 21929PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 219His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22029PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 220His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22129PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 221His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22229PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 222His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22329PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 223His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22429PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 224His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22529PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 225His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22629PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 226His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20

25 22729PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 227His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 22829PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 228His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Ala 20 25 22929PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 229His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Glu Ala 20 25 23029PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 230His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Glu Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23129PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 231His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Glu Trp Leu Lys Ser Thr 20 25 23229PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 232His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23329PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 233His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala His Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23429PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 234His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23529PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 235His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23629PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 236His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Lys Ala Asp Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23729PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 237His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Lys Asp Phe Val Ala Trp Leu Lys Ser Thr 20 25 23829PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 238His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Arg 1 5 10 15 Ala Arg Ala Asp Asp Phe Val Lys Trp Leu Lys Ser Thr 20 25 23929PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 239His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 24029PRTArtificial sequenceSynthetic sequence Derivatised peptide 'X' of PCT/DK2011/050018 240His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 24142PRTArtificial sequenceSynthetic sequence GLP-1 agonist exendin-4(1-39)-K6 241His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Ser Lys Lys Lys Lys Lys Lys 35 40 24228PRTArtificial sequenceSynthetic sequence Test peptide 242His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ala Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 24328PRTArtificial sequenceSynthetic sequence Test peptide 243His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Glu Arg Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 24428PRTArtificial sequenceSynthetic sequence Test peptide 244His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg His Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 24528PRTArtificial sequenceSynthetic sequence Test peptide 245His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Ser Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 24628PRTArtificial sequenceSynthetic sequence Test peptide 246His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 24728PRTArtificial sequenceSynthetic sequence Test peptide 247His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Tyr Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 24828PRTArtificial sequenceSynthetic sequence Test peptide 248His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Glu Ser Ala 20 25 24928PRTArtificial sequenceSynthetic sequence Test peptide 249His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Lys Ser Ala 20 25 25028PRTArtificial sequenceSynthetic sequence Test peptide 250His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Lys Arg Ala 20 25 25128PRTArtificial sequenceSynthetic sequence Test peptide 251His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Glu Arg Ala 20 25 25228PRTArtificial sequenceSynthetic sequence Test peptide 252His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Trp Leu Leu Asn Thr 20 25 25328PRTArtificial sequenceSynthetic sequence Test peptide 253His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Leu Asn Thr 20 25 25428PRTArtificial sequenceSynthetic sequence Test peptide 254His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Leu Asn Lys 20 25 25528PRTArtificial sequenceSynthetic sequence Test peptide 255His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Ala Leu Ala Gln Asp Phe Val Trp Leu Leu Asn Thr 20 25 25628PRTArtificial sequenceSynthetic sequence Test peptide 256His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Trp Leu Met Asn Thr 20 25 25728PRTArtificial sequenceSynthetic sequence Test peptide 257His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Trp Leu Met Asn Thr 20 25 25828PRTArtificial sequenceSynthetic sequence Test peptide 258His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 25928PRTArtificial sequenceSynthetic sequence Test peptide 259His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 26028PRTArtificial sequenceSynthetic sequence Test peptide 260His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala Gln Asp Phe Val Trp Leu Met Asn Thr 20 25 26129PRTArtificial sequenceSynthetic sequence Test peptide 261His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Lys Ala 20 25 26229PRTArtificial sequenceSynthetic sequence Test peptide 262His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 26329PRTArtificial sequenceSynthetic sequence Test peptide 263His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Lys Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Ser Ala 20 25 26429PRTArtificial sequenceSynthetic sequence 264His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 26529PRTArtificial sequenceSynthetic sequence 265His Ser Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 26629PRTArtificial sequenceSynthetic sequence 266His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Xaa Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 26729PRTArtificial sequenceSynthetic sequence 267His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Cys Arg Ala 20 25 26829PRTArtificial sequenceSynthetic sequence 268His Ala Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Arg Ala 20 25 26929PRTArtificial sequenceSynthetic sequence 269His Ala Gln Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Glu Phe Val Ala Trp Leu Leu Arg Ala 20 25 27029PRTArtificial sequenceSynthetic sequence 270His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27129PRTArtificial sequenceSynthetic sequence 271His Ala Gln Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27229PRTArtificial sequenceSynthetic sequence 272His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27335PRTArtificial sequenceSynthetic sequence 273His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Ile Glu Trp Leu Leu Ser Ala Lys Lys Lys 20 25 30 Lys Lys Lys 35 27429PRTArtificial sequenceSynthetic sequence 274His Gly Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27529PRTArtificial sequenceSynthetic sequence 275His Ala Gln Gly Thr Phe Thr Ser Ser Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27629PRTArtificial sequenceSynthetic sequence 276His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Ser Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27729PRTArtificial sequenceSynthetic sequence (cyclic) 277His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27829PRTArtificial sequenceSynthetic sequence 278His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 27929PRTArtificial sequenceSynthetic sequence 279His Gly Gln Ala Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28029PRTArtificial sequenceSynthetic sequence 280His Gly Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28129PRTArtificial sequenceSynthetic sequence 281His Ser Gln Ala Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28229PRTArtificial sequenceSynthetic sequence 282His Ala Gln Leu Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28329PRTArtificial sequenceSynthetic sequence 283His Ala Gln Pro Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28429PRTArtificial sequenceSynthetic sequence 284His Ala Gln Glu Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28529PRTArtificial sequenceSynthetic sequence 285His Ala Gln Ala Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28629PRTArtificial sequenceSynthetic sequence 286His Ala Gln Phe Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu

Ser Ala 20 25 28729PRTArtificial sequenceSynthetic sequence 287His Ala Phe Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28829PRTArtificial sequenceSynthetic sequence 288His Ala Gln Xaa Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 28929PRTArtificial sequenceSynthetic sequence 289His Ala Gln Arg Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29029PRTArtificial sequenceSynthetic sequence 290His Ala Leu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29129PRTArtificial sequenceSynthetic sequence 291His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29229PRTArtificial sequenceSynthetic sequence 292His Ala Trp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29329PRTArtificial sequenceSynthetic sequence 293His Ala Tyr Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29429PRTArtificial sequenceSynthetic sequence 294His Ala Val Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29529PRTArtificial sequenceSynthetic sequence 295His Ala Gln Lys Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29629PRTArtificial sequenceSynthetic sequence 296His Ala Arg Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29729PRTArtificial sequenceSynthetic sequence 297His Ala Ala Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29829PRTArtificial sequenceSynthetic sequence 298His Ala Ser Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 29929PRTArtificial sequenceSynthetic sequence 299His Ala Ile Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30029PRTArtificial sequenceSynthetic sequence 300His Ala Gly Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30129PRTArtificial sequenceSynthetic sequence 301His Ala Pro Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30229PRTArtificial sequenceSynthetic sequence 302His Ala His Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Glu Phe Val Glu Trp Leu Leu Glu Ala 20 25 30329PRTArtificial sequenceSynthetic sequence 303His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30429PRTArtificial sequenceSynthetic sequence 304His Ala Gln Xaa Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30529PRTArtificial sequenceSynthetic sequence 305His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30629PRTArtificial sequenceSynthetic sequence 306His Ala Gln Xaa Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30729PRTArtificial sequenceSynthetic sequence 307His Ala His Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Ser 1 5 10 15 Lys Ala Ala Glu Glu Phe Val Glu Trp Leu Leu Glu Ala 20 25 30829PRTArtificial sequenceSynthetic sequence 308His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 30929PRTArtificial sequenceSynthetic sequence 309His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31029PRTArtificial sequenceSynthetic sequence 310His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31129PRTArtificial sequenceSynthetic sequence 311His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31229PRTArtificial sequenceSynthetic sequence 312His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31329PRTArtificial sequenceSynthetic sequence 313His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31429PRTArtificial sequenceSynthetic sequence 314His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31529PRTArtificial sequenceSynthetic sequence 315His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31629PRTArtificial sequenceSynthetic sequence 316His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31729PRTArtificial sequenceSynthetic sequence 317His Ala His Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31829PRTArtificial sequenceSynthetic sequence 318His Ala Gln Xaa Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 31929PRTArtificial sequenceSynthetic sequence 319His Ala Tyr Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32029PRTArtificial sequenceSynthetic sequence 320His Ala Pro Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32129PRTArtificial sequenceSynthetic sequence 321His Ala His Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Glu Phe Val Glu Trp Leu Leu Glu Ala 20 25 32229PRTArtificial sequenceSynthetic sequence 322His Ala Gln Xaa Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32329PRTArtificial sequenceSynthetic sequence 323His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32429PRTArtificial sequenceSynthetic sequence 324His Ala Gln Ala Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32529PRTArtificial sequenceSynthetic sequence 325His Ser Gln Ala Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32629PRTArtificial sequenceSynthetic sequence 326His Ala Gln Glu Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32729PRTArtificial sequenceSynthetic sequence 327His Ala Gln Ala Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32829PRTArtificial sequenceSynthetic sequence 328His Ala Gln Phe Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 32929PRTArtificial sequenceSynthetic sequence 329His Ala Leu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33029PRTArtificial sequenceSynthetic sequence 330His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33129PRTArtificial sequenceSynthetic sequence 331His Ala Trp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33229PRTArtificial sequenceSynthetic sequence 332His Ala Val Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33329PRTArtificial sequenceSynthetic sequence 333His Ala Ala Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33429PRTArtificial sequenceSynthetic sequence 334His Ala Ser Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33529PRTArtificial sequenceSynthetic sequence 335His Ala Ile Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33629PRTArtificial sequenceSynthetic sequence 336His Ala Gly Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33729PRTArtificial sequenceSynthetic sequence 337His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33829PRTArtificial sequenceSynthetic sequence 338His Ala Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Lys Ala Ala His Asp Phe Val Glu Trp Leu Leu Ser Ala 20 25 33910PRTArtificial sequenceSynthetic sequence 'Z1' in PCT/DK2011/050018 339Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 34011PRTArtificial sequenceSynthetic sequence 'Z1' in PCT/DK2011/050018 340Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Cys 1 5 10 3418PRTArtificial sequenceSynthetic sequence 'Z1' in PCT/DK2011/050018 341Lys Arg Asn Arg Asn Asn Ile Ala 1 5 3424PRTArtificial sequenceSynthetic sequence 'Z1' in PCT/DK2011/050018 342Lys Arg Asn Arg 1 34329PRTArtificial sequenceSynthetic sequence Formula VII in PCT/DK2011/050018 343Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Xaa Ser Xaa Tyr Leu Xaa Xaa 1 5 10 15 Xaa Xaa Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 34429PRTArtificial sequenceSynthetic sequence 344His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 34529PRTArtificial sequenceSynthetic sequence 345His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 34629PRTArtificial sequenceSynthetic sequence 346His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 34729PRTArtificial sequenceSynthetic sequence 347His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 34829PRTArtificial sequenceSynthetic sequence 348His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 34929PRTArtificial sequenceSynthetic sequence 349His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 35029PRTArtificial sequenceSynthetic sequence 350His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 35129PRTArtificial sequenceSynthetic sequence 351His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5

10 15 Arg Arg Ala Asp Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 35229PRTArtificial sequenceSynthetic sequence 352His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 35329PRTArtificial sequenceSynthetic sequence 353His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 35429PRTArtificial sequenceSynthetic sequence 354His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 35529PRTArtificial sequenceSynthetic sequence 355His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 35629PRTArtificial sequenceSynthetic sequence 356His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 35729PRTArtificial sequenceSynthetic sequence 357His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 35829PRTArtificial sequenceSynthetic sequence 358His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 35929PRTArtificial sequenceSynthetic sequence 359His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 36029PRTArtificial sequenceSynthetic sequence 360His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 36129PRTArtificial sequenceSynthetic sequence 361His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 36229PRTArtificial sequenceSynthetic sequence 362His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 36329PRTArtificial sequenceSynthetic sequence 363His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 36429PRTArtificial sequenceSynthetic sequence 364His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 36529PRTArtificial sequenceSynthetic sequence 365His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 36629PRTArtificial sequenceSynthetic sequence 366His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 36729PRTArtificial sequenceSynthetic sequence 367His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 36829PRTArtificial sequenceSynthetic sequence 368His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 36929PRTArtificial sequenceSynthetic sequence 369His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 37029PRTArtificial sequenceSynthetic sequence 370Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37129PRTArtificial sequenceSynthetic sequence 371Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37229PRTArtificial sequenceSynthetic sequence 372Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37329PRTArtificial sequenceSynthetic sequence 373Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37429PRTArtificial sequenceSynthetic sequence 374Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37529PRTArtificial sequenceSynthetic sequence 375Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37629PRTArtificial sequenceSynthetic sequence 376Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37729PRTArtificial sequenceSynthetic sequence 377Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37829PRTArtificial sequenceSynthetic sequence 378Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 37929PRTArtificial sequenceSynthetic sequence 379Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 38029PRTArtificial sequenceSynthetic sequence 380Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 38129PRTArtificial sequenceSynthetic sequence 381Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 38229PRTArtificial sequenceSynthetic sequence 382Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 38329PRTArtificial sequenceSynthetic sequence 383Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 38429PRTArtificial sequenceSynthetic sequence 384Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 38529PRTArtificial sequenceSynthetic sequence 385Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 38629PRTArtificial sequenceSynthetic sequence 386Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 38729PRTArtificial sequenceSynthetic sequence 387His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 38829PRTArtificial sequenceSynthetic sequence 388His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 38929PRTArtificial sequenceSynthetic sequence 389His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39029PRTArtificial sequenceSynthetic sequence 390His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39129PRTArtificial sequenceSynthetic sequence 391His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39229PRTArtificial sequenceSynthetic sequence 392His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39329PRTArtificial sequenceSynthetic sequence 393His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39429PRTArtificial sequenceSynthetic sequence 394His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39529PRTArtificial sequenceSynthetic sequence 395His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39629PRTArtificial sequenceSynthetic sequence 396His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39729PRTArtificial sequenceSynthetic sequence 397His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 39829PRTArtificial sequenceSynthetic sequence 398His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 39929PRTArtificial sequenceSynthetic sequence 399His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 40029PRTArtificial sequenceSynthetic sequence 400His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 40129PRTArtificial sequenceSynthetic sequence 401His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 40229PRTArtificial sequenceSynthetic sequence 402His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 40329PRTArtificial sequenceSynthetic sequence 403His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 40429PRTArtificial sequenceSynthetic sequence 404His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 40529PRTArtificial sequenceSynthetic sequence 405His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 40629PRTArtificial sequenceSynthetic sequence 406His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 40729PRTArtificial sequenceSynthetic sequence 407His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 40829PRTArtificial sequenceSynthetic sequence 408His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 40929PRTArtificial sequenceSynthetic sequence 409His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 41029PRTArtificial sequenceSynthetic sequence 410His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 41129PRTArtificial sequenceSynthetic sequence 411His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 41229PRTArtificial sequenceSynthetic sequence 412His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 41329PRTArtificial sequenceSynthetic sequence 413His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 41429PRTArtificial sequenceSynthetic sequence 414His Xaa Gln Gly Thr Phe

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 41529PRTArtificial sequenceSynthetic sequence 415His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 41629PRTArtificial sequenceSynthetic sequence 416His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 41729PRTArtificial sequenceSynthetic sequence 417His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 41829PRTArtificial sequenceSynthetic sequence 418His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 41929PRTArtificial sequenceSynthetic sequence 419His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 42029PRTArtificial sequenceSynthetic sequence 420His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 42129PRTArtificial sequenceSynthetic sequence 421His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42229PRTArtificial sequenceSynthetic sequence 422His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42329PRTArtificial sequenceSynthetic sequence 423His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42429PRTArtificial sequenceSynthetic sequence 424His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42529PRTArtificial sequenceSynthetic sequence 425His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42629PRTArtificial sequenceSynthetic sequence 426His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42729PRTArtificial sequenceSynthetic sequence 427His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42829PRTArtificial sequenceSynthetic sequence 428His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 42929PRTArtificial sequenceSynthetic sequence 429His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 43029PRTArtificial sequenceSynthetic sequence 430His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 43129PRTArtificial sequenceSynthetic sequence 431His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 43229PRTArtificial sequenceSynthetic sequence 432His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 43329PRTArtificial sequenceSynthetic sequence 433His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 43429PRTArtificial sequenceSynthetic sequence 434His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 43529PRTArtificial sequenceSynthetic sequence 435His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 43629PRTArtificial sequenceSynthetic sequence 436His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 43729PRTArtificial sequenceSynthetic sequence 437His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 43829PRTArtificial sequenceSynthetic sequence 438Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 43929PRTArtificial sequenceSynthetic sequence 439Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44029PRTArtificial sequenceSynthetic sequence 440Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44129PRTArtificial sequenceSynthetic sequence 441Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44229PRTArtificial sequenceSynthetic sequence 442Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44329PRTArtificial sequenceSynthetic sequence 443Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44429PRTArtificial sequenceSynthetic sequence 444Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44529PRTArtificial sequenceSynthetic sequence 445Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44629PRTArtificial sequenceSynthetic sequence 446Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44729PRTArtificial sequenceSynthetic sequence 447Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44829PRTArtificial sequenceSynthetic sequence 448Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 44929PRTArtificial sequenceSynthetic sequence 449Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 45029PRTArtificial sequenceSynthetic sequence 450Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 45129PRTArtificial sequenceSynthetic sequence 451Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 45229PRTArtificial sequenceSynthetic sequence 452Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 45329PRTArtificial sequenceSynthetic sequence 453Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 45429PRTArtificial sequenceSynthetic sequence 454Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 45529PRTArtificial sequenceSynthetic sequence 455His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 45629PRTArtificial sequenceSynthetic sequence 456His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 45729PRTArtificial sequenceSynthetic sequence 457His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 45829PRTArtificial sequenceSynthetic sequence 458His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 45929PRTArtificial sequenceSynthetic sequence 459His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46029PRTArtificial sequenceSynthetic sequence 460His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46129PRTArtificial sequenceSynthetic sequence 461His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46229PRTArtificial sequenceSynthetic sequence 462His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46329PRTArtificial sequenceSynthetic sequence 463His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46429PRTArtificial sequenceSynthetic sequence 464His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46529PRTArtificial sequenceSynthetic sequence 465His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 46629PRTArtificial sequenceSynthetic sequence 466His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 46729PRTArtificial sequenceSynthetic sequence 467His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 46829PRTArtificial sequenceSynthetic sequence 468His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 46929PRTArtificial sequenceSynthetic sequence 469His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 47029PRTArtificial sequenceSynthetic sequence 470His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 47129PRTArtificial sequenceSynthetic sequence 471His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 47229PRTArtificial sequenceSynthetic sequence 472His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 47329PRTArtificial sequenceSynthetic sequence 473His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 47429PRTArtificial sequenceSynthetic sequence 474His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 47529PRTArtificial sequenceSynthetic sequence 475His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 47629PRTArtificial sequenceSynthetic sequence 476His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25

47729PRTArtificial sequenceSynthetic sequence 477His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 47829PRTArtificial sequenceSynthetic sequence 478His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 47929PRTArtificial sequenceSynthetic sequence 479His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 48029PRTArtificial sequenceSynthetic sequence 480His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 48129PRTArtificial sequenceSynthetic sequence 481His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 48229PRTArtificial sequenceSynthetic sequence 482His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 48329PRTArtificial sequenceSynthetic sequence 483His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 48429PRTArtificial sequenceSynthetic sequence 484His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 48529PRTArtificial sequenceSynthetic sequence 485His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 48629PRTArtificial sequenceSynthetic sequence 486His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 48729PRTArtificial sequenceSynthetic sequence 487His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 48829PRTArtificial sequenceSynthetic sequence 488His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 48929PRTArtificial sequenceSynthetic sequence 489His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49029PRTArtificial sequenceSynthetic sequence 490His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49129PRTArtificial sequenceSynthetic sequence 491His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49229PRTArtificial sequenceSynthetic sequence 492His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49329PRTArtificial sequenceSynthetic sequence 493His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49429PRTArtificial sequenceSynthetic sequence 494His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49529PRTArtificial sequenceSynthetic sequence 495His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49629PRTArtificial sequenceSynthetic sequence 496His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49729PRTArtificial sequenceSynthetic sequence 497His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49829PRTArtificial sequenceSynthetic sequence 498His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 49929PRTArtificial sequenceSynthetic sequence 499His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 50029PRTArtificial sequenceSynthetic sequence 500His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 50129PRTArtificial sequenceSynthetic sequence 501His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 50229PRTArtificial sequenceSynthetic sequence 502His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 50329PRTArtificial sequenceSynthetic sequence 503His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 50429PRTArtificial sequenceSynthetic sequence 504His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 50529PRTArtificial sequenceSynthetic sequence 505His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 50629PRTArtificial sequenceSynthetic sequence 506Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 50729PRTArtificial sequenceSynthetic sequence 507Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 50829PRTArtificial sequenceSynthetic sequence 508Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 50929PRTArtificial sequenceSynthetic sequence 509Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51029PRTArtificial sequenceSynthetic sequence 510Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51129PRTArtificial sequenceSynthetic sequence 511Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51229PRTArtificial sequenceSynthetic sequence 512Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51329PRTArtificial sequenceSynthetic sequence 513Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51429PRTArtificial sequenceSynthetic sequence 514Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51529PRTArtificial sequenceSynthetic sequence 515Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51629PRTArtificial sequenceSynthetic sequence 516Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 51729PRTArtificial sequenceSynthetic sequence 517Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 51829PRTArtificial sequenceSynthetic sequence 518Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 51929PRTArtificial sequenceSynthetic sequence 519Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 52029PRTArtificial sequenceSynthetic sequence 520Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 52129PRTArtificial sequenceSynthetic sequence 521Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 52229PRTArtificial sequenceSynthetic sequence 522Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 52329PRTArtificial sequenceSynthetic sequence 523His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 52429PRTArtificial sequenceSynthetic sequence 524His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 52529PRTArtificial sequenceSynthetic sequence 525His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 52629PRTArtificial sequenceSynthetic sequence 526His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 52729PRTArtificial sequenceSynthetic sequence 527His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 52829PRTArtificial sequenceSynthetic sequence 528His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 52929PRTArtificial sequenceSynthetic sequence 529His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 53029PRTArtificial sequenceSynthetic sequence 530His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 53129PRTArtificial sequenceSynthetic sequence 531His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 53229PRTArtificial sequenceSynthetic sequence 532His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 53329PRTArtificial sequenceSynthetic sequence 533His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 53429PRTArtificial sequenceSynthetic sequence 534His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 53529PRTArtificial sequenceSynthetic sequence 535His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 53629PRTArtificial sequenceSynthetic sequence 536His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 53729PRTArtificial sequenceSynthetic sequence 537His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 53829PRTArtificial sequenceSynthetic sequence 538His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 53929PRTArtificial sequenceSynthetic sequence 539His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val

Lys Gly 20 25 54029PRTArtificial sequenceSynthetic sequence 540His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54129PRTArtificial sequenceSynthetic sequence 541His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54229PRTArtificial sequenceSynthetic sequence 542His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54329PRTArtificial sequenceSynthetic sequence 543His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54429PRTArtificial sequenceSynthetic sequence 544His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54529PRTArtificial sequenceSynthetic sequence 545His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54629PRTArtificial sequenceSynthetic sequence 546His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54729PRTArtificial sequenceSynthetic sequence 547His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54829PRTArtificial sequenceSynthetic sequence 548His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 54929PRTArtificial sequenceSynthetic sequence 549His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 55029PRTArtificial sequenceSynthetic sequence 550His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 55129PRTArtificial sequenceSynthetic sequence 551His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 55229PRTArtificial sequenceSynthetic sequence 552His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 55329PRTArtificial sequenceSynthetic sequence 553His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 55429PRTArtificial sequenceSynthetic sequence 554His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 55529PRTArtificial sequenceSynthetic sequence 555His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 55629PRTArtificial sequenceSynthetic sequence 556His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 55729PRTArtificial sequenceSynthetic sequence 557His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 55829PRTArtificial sequenceSynthetic sequence 558His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 55929PRTArtificial sequenceSynthetic sequence 559His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56029PRTArtificial sequenceSynthetic sequence 560His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56129PRTArtificial sequenceSynthetic sequence 561His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56229PRTArtificial sequenceSynthetic sequence 562His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56329PRTArtificial sequenceSynthetic sequence 563His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56429PRTArtificial sequenceSynthetic sequence 564His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56529PRTArtificial sequenceSynthetic sequence 565His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56629PRTArtificial sequenceSynthetic sequence 566His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56729PRTArtificial sequenceSynthetic sequence 567His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 56829PRTArtificial sequenceSynthetic sequence 568His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 56929PRTArtificial sequenceSynthetic sequence 569His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 57029PRTArtificial sequenceSynthetic sequence 570His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 57129PRTArtificial sequenceSynthetic sequence 571His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 57229PRTArtificial sequenceSynthetic sequence 572His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 57329PRTArtificial sequenceSynthetic sequence 573His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 57429PRTArtificial sequenceSynthetic sequence 574Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 57529PRTArtificial sequenceSynthetic sequence 575Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 57629PRTArtificial sequenceSynthetic sequence 576Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 57729PRTArtificial sequenceSynthetic sequence 577Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 57829PRTArtificial sequenceSynthetic sequence 578Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 57929PRTArtificial sequenceSynthetic sequence 579Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 58029PRTArtificial sequenceSynthetic sequence 580Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 58129PRTArtificial sequenceSynthetic sequence 581Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 58229PRTArtificial sequenceSynthetic sequence 582Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 58329PRTArtificial sequenceSynthetic sequence 583Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 58429PRTArtificial sequenceSynthetic sequence 584Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 58529PRTArtificial sequenceSynthetic sequence 585Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 58629PRTArtificial sequenceSynthetic sequence 586Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 58729PRTArtificial sequenceSynthetic sequence 587Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 58829PRTArtificial sequenceSynthetic sequence 588Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 58929PRTArtificial sequenceSynthetic sequence 589Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 59029PRTArtificial sequenceSynthetic sequence 590Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 59129PRTArtificial sequenceSynthetic sequence 591His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59229PRTArtificial sequenceSynthetic sequence 592His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59329PRTArtificial sequenceSynthetic sequence 593His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59429PRTArtificial sequenceSynthetic sequence 594His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59529PRTArtificial sequenceSynthetic sequence 595His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59629PRTArtificial sequenceSynthetic sequence 596His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59729PRTArtificial sequenceSynthetic sequence 597His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59829PRTArtificial sequenceSynthetic sequence 598His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 59929PRTArtificial sequenceSynthetic sequence 599His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 60029PRTArtificial sequenceSynthetic sequence 600His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 60129PRTArtificial sequenceSynthetic sequence 601His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 60229PRTArtificial sequenceSynthetic sequence 602His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5

10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 60329PRTArtificial sequenceSynthetic sequence 603His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 60429PRTArtificial sequenceSynthetic sequence 604His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 60529PRTArtificial sequenceSynthetic sequence 605His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 60629PRTArtificial sequenceSynthetic sequence 606His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 60729PRTArtificial sequenceSynthetic sequence 607His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 60829PRTArtificial sequenceSynthetic sequence 608His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 60929PRTArtificial sequenceSynthetic sequence 609His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61029PRTArtificial sequenceSynthetic sequence 610His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61129PRTArtificial sequenceSynthetic sequence 611His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61229PRTArtificial sequenceSynthetic sequence 612His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61329PRTArtificial sequenceSynthetic sequence 613His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61429PRTArtificial sequenceSynthetic sequence 614His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61529PRTArtificial sequenceSynthetic sequence 615His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61629PRTArtificial sequenceSynthetic sequence 616His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61729PRTArtificial sequenceSynthetic sequence 617His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61829PRTArtificial sequenceSynthetic sequence 618His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 61929PRTArtificial sequenceSynthetic sequence 619His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 62029PRTArtificial sequenceSynthetic sequence 620His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 62129PRTArtificial sequenceSynthetic sequence 621His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 62229PRTArtificial sequenceSynthetic sequence 622His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 62329PRTArtificial sequenceSynthetic sequence 623His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 62429PRTArtificial sequenceSynthetic sequence 624His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly 20 25 62529PRTArtificial sequenceSynthetic sequence 625His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 62629PRTArtificial sequenceSynthetic sequence 626His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 62729PRTArtificial sequenceSynthetic sequence 627His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 62829PRTArtificial sequenceSynthetic sequence 628His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 62929PRTArtificial sequenceSynthetic sequence 629Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 63029PRTArtificial sequenceSynthetic sequence 630Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 63129PRTArtificial sequenceSynthetic sequence 631Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 63229PRTArtificial sequenceSynthetic sequence 632Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 63329PRTArtificial sequenceSynthetic sequence 633His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 63429PRTArtificial sequenceSynthetic sequence 634His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 63529PRTArtificial sequenceSynthetic sequence 635His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 63629PRTArtificial sequenceSynthetic sequence 636His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 63729PRTArtificial sequenceSynthetic sequence 637His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 63829PRTArtificial sequenceSynthetic sequence 638His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 63929PRTArtificial sequenceSynthetic sequence 639His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 64029PRTArtificial sequenceSynthetic sequence 640His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 64129PRTArtificial sequenceSynthetic sequence 641His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 64229PRTArtificial sequenceSynthetic sequence 642His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 64329PRTArtificial sequenceSynthetic sequence 643His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 64429PRTArtificial sequenceSynthetic sequence 644His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 64529PRTArtificial sequenceSynthetic sequence 645Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 64629PRTArtificial sequenceSynthetic sequence 646Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 64729PRTArtificial sequenceSynthetic sequence 647Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 64829PRTArtificial sequenceSynthetic sequence 648Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 64929PRTArtificial sequenceSynthetic sequence 649His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 65029PRTArtificial sequenceSynthetic sequence 650His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 65129PRTArtificial sequenceSynthetic sequence 651His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 65229PRTArtificial sequenceSynthetic sequence 652His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 65329PRTArtificial sequenceSynthetic sequence 653His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 65429PRTArtificial sequenceSynthetic sequence 654His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr 20 25 65529PRTArtificial sequenceSynthetic sequence 655His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Thr 20 25 65629PRTArtificial sequenceSynthetic sequence 656His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly 20 25 65729PRTArtificial sequenceSynthetic sequence 657His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 65829PRTArtificial sequenceSynthetic sequence 658His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 65929PRTArtificial sequenceSynthetic sequence 659His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66029PRTArtificial sequenceSynthetic sequence 660His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66129PRTArtificial sequenceSynthetic sequence 661His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66229PRTArtificial sequenceSynthetic sequence 662His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66329PRTArtificial sequenceSynthetic sequence 663His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66429PRTArtificial sequenceSynthetic sequence 664His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66529PRTArtificial sequenceSynthetic sequence 665His Ser Gln Gly Thr Phe

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66629PRTArtificial sequenceSynthetic sequence 666His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66729PRTArtificial sequenceSynthetic sequence 667His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 66829PRTArtificial sequenceSynthetic sequence 668His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 66929PRTArtificial sequenceSynthetic sequence 669His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 67029PRTArtificial sequenceSynthetic sequence 670His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 67129PRTArtificial sequenceSynthetic sequence 671Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67229PRTArtificial sequenceSynthetic sequence 672Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67329PRTArtificial sequenceSynthetic sequence 673Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67429PRTArtificial sequenceSynthetic sequence 674Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67529PRTArtificial sequenceSynthetic sequence 675Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67629PRTArtificial sequenceSynthetic sequence 676Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67729PRTArtificial sequenceSynthetic sequence 677Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67829PRTArtificial sequenceSynthetic sequence 678Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 67929PRTArtificial sequenceSynthetic sequence 679Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68029PRTArtificial sequenceSynthetic sequence 680Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68129PRTArtificial sequenceSynthetic sequence 681Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68229PRTArtificial sequenceSynthetic sequence 682Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 68329PRTArtificial sequenceSynthetic sequence 683Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 68429PRTArtificial sequenceSynthetic sequence 684Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 68529PRTArtificial sequenceSynthetic sequence 685His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68629PRTArtificial sequenceSynthetic sequence 686His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68729PRTArtificial sequenceSynthetic sequence 687His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68829PRTArtificial sequenceSynthetic sequence 688His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 68929PRTArtificial sequenceSynthetic sequence 689His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69029PRTArtificial sequenceSynthetic sequence 690His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69129PRTArtificial sequenceSynthetic sequence 691His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69229PRTArtificial sequenceSynthetic sequence 692His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69329PRTArtificial sequenceSynthetic sequence 693His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69429PRTArtificial sequenceSynthetic sequence 694His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69529PRTArtificial sequenceSynthetic sequence 695His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 69629PRTArtificial sequenceSynthetic sequence 696His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 69729PRTArtificial sequenceSynthetic sequence 697His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 69829PRTArtificial sequenceSynthetic sequence 698His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 69929PRTArtificial sequenceSynthetic sequence 699His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70029PRTArtificial sequenceSynthetic sequence 700His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70129PRTArtificial sequenceSynthetic sequence 701His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70229PRTArtificial sequenceSynthetic sequence 702His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70329PRTArtificial sequenceSynthetic sequence 703His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70429PRTArtificial sequenceSynthetic sequence 704His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70529PRTArtificial sequenceSynthetic sequence 705His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70629PRTArtificial sequenceSynthetic sequence 706His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70729PRTArtificial sequenceSynthetic sequence 707His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70829PRTArtificial sequenceSynthetic sequence 708His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 70929PRTArtificial sequenceSynthetic sequence 709His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71029PRTArtificial sequenceSynthetic sequence 710His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 71129PRTArtificial sequenceSynthetic sequence 711His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 71229PRTArtificial sequenceSynthetic sequence 712His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 71329PRTArtificial sequenceSynthetic sequence 713His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71429PRTArtificial sequenceSynthetic sequence 714His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71529PRTArtificial sequenceSynthetic sequence 715His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71629PRTArtificial sequenceSynthetic sequence 716His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71729PRTArtificial sequenceSynthetic sequence 717His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71829PRTArtificial sequenceSynthetic sequence 718His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 71929PRTArtificial sequenceSynthetic sequence 719His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 72029PRTArtificial sequenceSynthetic sequence 720His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 72129PRTArtificial sequenceSynthetic sequence 721His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 72229PRTArtificial sequenceSynthetic sequence 722His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 72329PRTArtificial sequenceSynthetic sequence 723His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 72429PRTArtificial sequenceSynthetic sequence 724His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 72529PRTArtificial sequenceSynthetic sequence 725His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 72629PRTArtificial sequenceSynthetic sequence 726His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 72729PRTArtificial sequenceSynthetic sequence 727Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25

72829PRTArtificial sequenceSynthetic sequence 728Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 72929PRTArtificial sequenceSynthetic sequence 729Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73029PRTArtificial sequenceSynthetic sequence 730Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73129PRTArtificial sequenceSynthetic sequence 731Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73229PRTArtificial sequenceSynthetic sequence 732Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73329PRTArtificial sequenceSynthetic sequence 733Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73429PRTArtificial sequenceSynthetic sequence 734Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73529PRTArtificial sequenceSynthetic sequence 735Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73629PRTArtificial sequenceSynthetic sequence 736Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73729PRTArtificial sequenceSynthetic sequence 737Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 73829PRTArtificial sequenceSynthetic sequence 738Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 73929PRTArtificial sequenceSynthetic sequence 739Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 74029PRTArtificial sequenceSynthetic sequence 740Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 74129PRTArtificial sequenceSynthetic sequence 741His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74229PRTArtificial sequenceSynthetic sequence 742His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74329PRTArtificial sequenceSynthetic sequence 743His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74429PRTArtificial sequenceSynthetic sequence 744His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74529PRTArtificial sequenceSynthetic sequence 745His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74629PRTArtificial sequenceSynthetic sequence 746His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74729PRTArtificial sequenceSynthetic sequence 747His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74829PRTArtificial sequenceSynthetic sequence 748His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 74929PRTArtificial sequenceSynthetic sequence 749His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75029PRTArtificial sequenceSynthetic sequence 750His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75129PRTArtificial sequenceSynthetic sequence 751His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75229PRTArtificial sequenceSynthetic sequence 752His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 75329PRTArtificial sequenceSynthetic sequence 753His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 75429PRTArtificial sequenceSynthetic sequence 754His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 75528PRTArtificial sequenceSynthetic sequence 755His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75629PRTArtificial sequenceSynthetic sequence 756His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75729PRTArtificial sequenceSynthetic sequence 757His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75828PRTArtificial sequenceSynthetic sequence 758His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 75929PRTArtificial sequenceSynthetic sequence 759His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76029PRTArtificial sequenceSynthetic sequence 760His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76129PRTArtificial sequenceSynthetic sequence 761His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76229PRTArtificial sequenceSynthetic sequence 762His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76328PRTArtificial sequenceSynthetic sequence 763His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76429PRTArtificial sequenceSynthetic sequence 764His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76529PRTArtificial sequenceSynthetic sequence 765His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Ala Ala Glu Asp Phe Val Gln Trp Leu Met Asp Thr 20 25 76629PRTArtificial sequenceSynthetic sequence 766His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 76729PRTArtificial sequenceSynthetic sequence 767His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 76829PRTArtificial sequenceSynthetic sequence 768His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asp Thr 20 25 76929PRTArtificial sequenceSynthetic sequence 769His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 77029PRTArtificial sequenceSynthetic sequence 770His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Cys 20 25 77140PRTArtificial sequenceSynthetic sequence 771His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 77240PRTArtificial sequenceSynthetic sequence 772His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 77339PRTArtificial sequenceSynthetic sequence 773His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 77439PRTArtificial sequenceSynthetic sequence 774His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 77529PRTArtificial sequenceSynthetic sequence 775His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 77629PRTArtificial sequenceSynthetic sequence 776His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Cys 20 25 77740PRTArtificial sequenceSynthetic sequence 777His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 77840PRTArtificial sequenceSynthetic sequence 778His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 77939PRTArtificial sequenceSynthetic sequence 779His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 78039PRTArtificial sequenceSynthetic sequence 780His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 78129PRTArtificial sequenceSynthetic sequence 781His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 78229PRTArtificial sequenceSynthetic sequence 782His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Cys 20 25 78340PRTArtificial sequenceSynthetic sequence 783His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 78440PRTArtificial sequenceSynthetic sequence 784His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 78539PRTArtificial sequenceSynthetic sequence 785His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 78639PRTArtificial sequenceSynthetic sequence 786His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 78729PRTArtificial sequenceSynthetic sequence 787His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25

78829PRTArtificial sequenceSynthetic sequence 788Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25 78929PRTArtificial sequenceSynthetic sequence 789Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Cys 20 25 79040PRTArtificial sequenceSynthetic sequence 790Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 79140PRTArtificial sequenceSynthetic sequence 791Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40 79239PRTArtificial sequenceSynthetic sequence 792Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 79329PRTArtificial sequenceSynthetic sequence 793Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 79429PRTArtificial sequenceSynthetic sequence 794His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 79529PRTArtificial sequenceSynthetic sequence 795Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Cys 20 25 79639PRTArtificial sequenceSynthetic sequence 796Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35 79728PRTArtificial sequenceSynthetic sequence 797Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Gln 1 5 10 15 Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Thr 20 25

Claims

1. A method of treating heart disease or heart dysfunction in a subject, comprising administering a glucagon-GLP-1 dual agonist to the subject as a positive inotropic agent.

2. The method according to claim 1, wherein said heart disease or heart dysfunction is selected from the group consisting of: congestive heart failure, systolic dysfunction, diastolic dysfunction, myocardial infarction, ischemic heart disease, diabetic cardiomyopathy and combinations thereof.

3-4. (canceled)

5. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist is administered in combination with an agent for treatment of a condition selected from heart failure, diabetes, obesity, myocardial infarction, hypolipidemia and hypertension.

6. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist is a compound having the formula: R.sup.1--X--Z.sup.1--Z.sup.2--R.sup.2 wherein: R.sup.1 is hydrogen, C.sub.1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl; X has the Formula I: TABLE-US-00072 SEQ ID NO: 105 X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-Tyr-Leu-X15-X16- X17-X18-Ala-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, acetyl-His, homo-His, alpha,alpha-dimethyl imidiazole acetic acid (DMIA), N-methyl His, alpha-methyl His or imidazole acetic acid; X2 is Ser, Aib or D-Ser; X3 is Gln, Glu, Orn or Nle; X10 is Tyr or Trp; X12 is Lys, Arg, His, Ala, Leu, Dpu, Dpr, Orn, Citrulline or Ornithine; X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid; X16 is Ser, Thr, Lys, Arg, His, Glu, Asp, Ala, Gly, Gln, homoglutamic acid or homocysteic acid; X17 is Arg, Lys, His, Glu, Gln, Ala, Leu, Dpu, Dpr, Orn, Cys, homocysteine or acetyl phenylalanine; X18 is Arg, Lys, His, Tyr, Ala, Ser, Leu, Cys, Orn, homocysteine or acetyl phenylalanine; X20 is Gln, Lys, Arg, His, Glu, Asp, Ala, Cys, Orn or Citrulline; X21 is Asp, Glu, Gln, Lys, Cys, Orn, homocysteine or acetyl phenyalanine; X23 is Val, Ile or Leu; X24 is Gln, Lys, Arg, Glu, Asp, Ser, Ala, Leu, Cys, Orn, homocysteine or acetyl phenyalanine; X27 is Met, Lys, Arg, Glu, Leu, Nle, Cys or absent; X28 is Asn, Lys, Arg, Glu, Asp, Ser, Ala, Leu, Cys, Citrulline, Orn, or absent; X29 is Thr, Lys, Arg, Glu, Ser, Ala, Gly, Cys, Orn, homocysteine, acetyl phenyalanine or absent; R.sup.2 is NH.sub.2 or OH; Z.sup.1 is absent or has the sequence: TABLE-US-00073 Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser; Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Cys; Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala; or Lys Arg Asn Arg;

Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; wherein, if Z.sup.1 is present, X27, X28 and X29 are also present; and if Z.sup.1 is absent, the compound has a substitution or deletion relative to human glucagon at one or more of positions X1, X2, X3, X10, X12, X15, X16, X17, X18, X20, X21, X23, X24, X27, X28 and X29; or a pharmaceutically acceptable salt or derivative thereof; wherein said compound has higher GLP-1 receptor selectivity than human glucagon.

7-29. (canceled)

30. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R.sup.1--X--Z.sup.2--R.sup.2 wherein R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; R.sup.2 is OH or NH.sub.2; X is a peptide which has the Formula III: TABLE-US-00074 SEQ ID NO: 13 His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Leu-Tyr-Leu-Asp- Ser-Arg-Arg-Ala-Lys-Asp-Phe-Ile-Glu-Trp-Leu-Glu-Ser-Ala

or differs from Formula III at up to 4 of the following positions whereby, if different from Formula III: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly, Asp; the residue at position 17 is selected from: Lys, Leu; the residue at position 18 is selected from Lys, His, Ala, Ser, Tyr; the residue at position 20 is selected from: Gln, His, Arg, Glu, Asp; the residue at position 21 is: Glu; the residue at position 23 is selected from: Val, Leu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp; the residue at position 27 is selected from Met, Cys, Lys, Arg, Leu or is absent the residue at position 28 is selected from Asn, Arg, Lys, Glu, Ala, Leu, Asp or'is absent and the residue at position 29 is selected from Thr, Glu, Lys or is absent and Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

31-40. (canceled)

41. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R.sup.1--X--Z.sup.2--R.sup.2 wherein R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; R.sup.2 is OH or NH.sub.2; X is a peptide which has the Formula V: TABLE-US-00075 SEQ ID NO: 36 His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Lys-Ala-Al- a-His-Asp-Phe-Val-Glu-Trp- Leu-Leu-Arg-Ala

or differs from Formula V at up to 4 of the following positions whereby, if different from Formula V: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 12 is selected from: Leu, Arg, Dpu, Dpr, Orn; the residue at position 16 is selected from: Arg, His, Lys, Glu, Asp; the residue at position 17 is selected from: Arg, Leu, Dpu, Dpr, Orn; the residue at position 18 is selected from: Arg, Lys, His, Ser, Tyr; the residue at position 20 is selected from: Gln, Lys, Arg, Glu, Asp; the residue at position 21 is Glu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu or is absent; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu, Asp or is absent; and the residue at position 29 is selected from: Thr, Glu, Lys or is absent; and Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

42-45. (canceled)

46. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R.sup.1--X--Z.sup.2--R.sup.2 wherein R.sup.1 is H, C.sub.1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; R.sup.2 is OH or NH.sub.2; X is a peptide which has the Formula VI: TABLE-US-00076 SEQ ID NO: 49 His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp- Ser-Lys-Ala-Ala-His-Asp-Phe-Val-Glu-Trp-Leu-Leu-Arg-Ala

or differs from Formula VI at up to 5 of the following positions whereby, if different from Formula VI: the residue at position 2 is selected from: Aib, D-Ser; the residue at position 16 is selected from: Arg, His, Lys, Glu; the residue at position 17 is: Arg, Leu, Dpu, Dpr, Orn; the residue at position 20 is selected from: Gln, Lys, Arg, Glu, Asp; the residue at position 21 is Glu; the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp; the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu or is absent; the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu, Asp or is absent; and the residue at position 29 is selected from: Thr, Glu, Lys or is absent; and Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn; or a pharmaceutically acceptable salt thereof.

47-53. (canceled)

54. The method according to claim 1, wherein the glucagon-GLP-1 dual agonist has the formula R.sup.1--X--Z.sup.1--Z.sup.2--R.sup.2 wherein: R.sup.1 is hydrogen, C.sub.1-4 alkyl (e.g. methyl), acetyl, formyl, benzoyl or trifluoroacetyl; wherein X has the Formula VII: TABLE-US-00077 SEQ ID NO: 343 X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-Tyr-Leu-X15-X16- X17-X18-Ala-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29

wherein X1 is His, D-His, (Des-amino)His, hydroxyl-His, acetyl-His, homo-His, alpha,alpha-dimethyl imidiazole acetic acid (DMIA), N-methyl His, alpha-methyl His, or imidazole acetic acid; X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, aminoisobutyric acid (Aib) or N-methyl Ala; X3 is Gln, Glu, Orn or Nle; X10 is Tyr or Trp; X12 is Lys, Citrulline, Orn or Arg; X15 is Asp, Glu, cysteic acid, homoglutamic acid or homocysteic acid; X16 is Ser, Glu, Gln, homoglutamic acid or homocysteic acid; X17 is Arg, Gln, Lys, Cys, Orn, homocysteine or acetyl phenylalanine; X18 is Arg, Ala, Lys, Cys, Orn, homocysteine or acetyl phenylalanine; X20 is Gln, Lys, Arg, Orn or Citrulline; X21 is Gln, Glu, Asp, Lys, Cys, Orn, homocysteine or acetyl phenyalanine; X23 is Val or Ile; X24 is Ala, Gln, Glu, Lys, Cys, Orn, homocysteine or acetyl phenyalanine; X27 is Met, Leu or Nle; X28 is Asn, Arg, Citrulline, Orn, Lys or Asp; X29 is Thr, Gly, Lys, Cys, Orn, homocysteine or acetyl phenyalanine; R.sup.2 is NH.sub.2 or OH; Z.sup.1 is absent or has the sequence: TABLE-US-00078 Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser; Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Cys; Lys-Arg-Asn-Arg-Asn-Asn-lle-Ala; or Lys Arg Asn Arg;

Z.sup.2 is absent or a peptide sequence of 1-20 amino acid units selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met, Har, Dbu, Dpr and Orn; wherein, if Z.sup.1 is absent, the compound has a substitution or deletion relative to human glucagon at one or more of positions X1, X2, X3, X10, X12, X15, X16, X17, X18, X20, X21, X23, X24, X27, X28 and X29; or a pharmaceutically acceptable salt or derivative thereof; wherein said compound has higher GLP-1 receptor selectivity than human glucagon and/or wherein the compound exhibits at least 20% of the activity of native GLP-1 at the GLP-1 receptor.

55. The method according to claim 54, wherein X differs from Formula VII by 1 to 3 amino acid modifications at positions selected from 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, 24, 27, 28 and 29.

56-118. (canceled)

119. The method according to claim 6, wherein Z.sup.2 is absent.

120. The method according to claim 6, wherein Z.sup.1 is absent.

121-122. (canceled)

123. The method according to claim 6, wherein one or more of the amino acid side chains of the glucagon-GLP-1 agonist is conjugated to a lipophilic substituent.

124-133. (canceled)

134. The method according to claim 123, wherein each lipophilic substituent comprises a lipophilic moiety conjugated to the amino acid side chain by a spacer.

135. A method according to claim 134 wherein the combination of lipophilic moiety and spacer is selected from dodecanoyl-.gamma.-Glu, hexadecanoyl-.gamma.-Glu, hexadecanoyl-Glu, hexadecanoyl-[3-aminopropanoyl], hexadecanoyl-[8-aminooctanoyl], hexadecanoyl-.epsilon.-Lys, 2-butyloctanoyl-.gamma.-Glu, octadecanoyl-.gamma.-Glu and hexadecanoyl-[4-aminobutanoyl].

136-154. (canceled)